1
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Li D, Ho V, Teng CF, Tsai HW, Liu Y, Bae S, Ajoyan H, Wettengel JM, Protzer U, Gloss BS, Rockett RJ, Al Asady R, Li J, So S, George J, Douglas MW, Tu T. Novel digital droplet inverse PCR assay shows that natural clearance of hepatitis B infection is associated with fewer viral integrations. Emerg Microbes Infect 2025; 14:2450025. [PMID: 39749570 PMCID: PMC11731057 DOI: 10.1080/22221751.2025.2450025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/30/2024] [Accepted: 01/01/2025] [Indexed: 01/04/2025]
Abstract
Hepatitis B virus (HBV) DNA integration into the host cell genome is reportedly a major cause of liver cancer, and a source of hepatitis B surface antigen (HBsAg). High HBsAg levels can alter immune responses which therefore contributes to the progression of HBV-related disease. However, to what extent integration leads to the persistent circulating HBsAg is unclear. Here, we aimed to determine if the extent of HBV DNA integration is associated with the persistence of circulating HBsAg in people exposed to HBV. We established a digital droplet quantitative inverse PCR (dd-qinvPCR) method to quantify integrated HBV DNA in patients who had been exposed to HBV (anti-HBc positive and HBeAg-negative). Total DNA extracts from both liver resections (n = 32; 14 HBsAg-negative and 18 HBsAg-positive) and fine-needle aspirates (FNA, n = 10; 2 HBsAg-negative and 8 HBsAg-positive) were analysed. Using defined in vitro samples for assay establishment, we showed that dd-qinvPCR could detect integrations within an input of <80 cells. The frequency of integrated HBV DNA in those who had undergone HBsAg loss (n = 14, mean ± SD of 1.514 × 10-3 ± 1.839 × 10-3 integrations per cell) was on average 9-fold lower than those with active HBV infection (n = 18, 1.16 × 10-2 ± 1.76 × 10-2 integrations per cell; p = 0.0179). In conclusion, we have developed and validated a highly precise, sensitive and quantitative PCR-based method for the quantification of HBV integrations in clinical samples. Natural clearance of HBV is associated with fewer viral integrations. Future studies are needed to determine if dynamics of integrated HBV DNA can inform the development of curative therapies.
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Affiliation(s)
- Dong Li
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Vikki Ho
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Chiao-Fang Teng
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yuanyuan Liu
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Sarah Bae
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Harout Ajoyan
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Jochen M. Wettengel
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Brian S. Gloss
- Scientific Platforms, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia
| | - Rebecca J. Rockett
- Centre for Infectious Diseases and Microbiology–Public Health, Westmead Hospital, Westmead, NSW, Australia
| | - Rafid Al Asady
- Department of Radiology, Westmead Hospital, Westmead, NSW, Australia
| | - Jane Li
- Department of Radiology, Westmead Hospital, Westmead, NSW, Australia
| | - Simon So
- Department of Radiology, Westmead Hospital, Westmead, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Mark W. Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
| | - Thomas Tu
- Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW, Australia
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2
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Yan Z, He M, He L, Wei L, Zhang Y. RNA m 6A methylation patterns in hepatocellular carcinoma and their association with characteristics of the tumor microenvironment and prognosis. Discov Oncol 2025; 16:1094. [PMID: 40515874 PMCID: PMC12167406 DOI: 10.1007/s12672-025-02965-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 06/10/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Methylation at the N6 atom of adenosine (m6A) of RNA has been linked to immune responses to various types of tumors. How m6A methylation affects tumorigenicity, progression, and tumor microenvironment in hepatocellular carcinoma (HCC) is unclear. METHODS Consensus clustering was used to define m6A methylation patterns based on expression of 26 regulatory factors in HCC. The relative abundance of various immune cell types in the tumor microenvironment was quantified using single-sample gene set enrichment analysis. Cox regression with LASSO was used to screen for genes whose expression correlated with survival of patients with HCC. RESULTS Two patterns of m6A methylation in HCC were identified: pattern C1 was associated with abundant tumor infiltration by activated CD8+ T cells and by effector memory CD8+ T cells, as well as longer survival; pattern C2 was associated with abundant tumor infiltration by activated CD4+ T cells and by type 2 helper T cells, as well as with shorter survival. Cox regression identified a seven-gene signature capable of predicting the characteristics of the tumor microenvironment and overall survival in HCC: patients in the high-risk group had a lower immunophenoscore, higher TIDE score, and worse survival. CONCLUSIONS Patterns of m6A methylation in HCC are related to immune cell characteristics of the tumor microenvironment and to disease progression and prognosis. Analyzing these patterns in detail may clarify when and how the HCC responds to checkpoint inhibitors and guide the personalization of immunotherapy.
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Affiliation(s)
- Zongcai Yan
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, Guangxi, People's Republic of China
| | - Meiling He
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, Guangxi, People's Republic of China
| | - Lifeng He
- Department of Thoracic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530000, Guangxi, People's Republic of China
| | - Liuxia Wei
- Department of Oncology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, 530011, Guangxi, People's Republic of China
| | - Yumei Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, Guangxi, People's Republic of China.
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3
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Xie C, Singal AK. Beyond the Cure: Navigating Hepatocellular Risk and Surveillance after Hepatitis C Eradication in the Direct-acting Antiviral Era. J Clin Transl Hepatol 2025; 13:418-424. [PMID: 40385945 PMCID: PMC12078169 DOI: 10.14218/jcth.2024.00499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 05/20/2025] Open
Abstract
Direct-acting antivirals (DAAs) have dramatically changed the landscape of chronic hepatitis C virus (HCV) treatment and significantly reduced the risk of HCV-related hepatocellular carcinoma (HCC) after achieving sustained virologic response. However, the risk of HCC persists, particularly in patients with pre-treatment cirrhosis or fibrosis stage 3 (F3), even after DAA-induced viral eradication. While professional guidelines agree on the need for surveillance in cirrhotic patients, there is no consensus regarding surveillance for the pre-treatment F3 population following HCV eradication. The risk of HCC in the F3 population falls below the threshold for cost-effective surveillance. However, co-existing risk factors-such as diabetes, hepatic steatosis, alcohol use, advanced age, and elevated alpha-fetoprotein levels-may warrant reconsideration of HCC surveillance in this group. This underscores the need for an individualized, risk-based approach to HCC surveillance. This review provided a simplified algorithm to assist clinicians in managing patients with HCV after DAA-induced sustained virologic response.
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Affiliation(s)
- Chencheng Xie
- Department of Gastroenterology, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
| | - Ashwani K. Singal
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
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4
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Otlu B, Alexandrov LB. Evaluating topography of mutational signatures with SigProfilerTopography. Genome Biol 2025; 26:134. [PMID: 40394581 PMCID: PMC12093824 DOI: 10.1186/s13059-025-03612-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 05/08/2025] [Indexed: 05/22/2025] Open
Abstract
The mutations found in a cancer genome are shaped by diverse processes, each displaying a characteristic mutational signature that may be influenced by the genome's architecture. While prior analyses have evaluated the effect of topographical genomic features on mutational signatures, there has been no computational tool that can comprehensively examine this interplay. Here, we present SigProfilerTopography, a Python package that allows evaluating the effect of chromatin organization, histone modifications, transcription factor binding, DNA replication, and DNA transcription on the activities of different mutational processes. SigProfilerTopography elucidates the unique topographical characteristics of mutational signatures, unveiling their underlying biological and molecular mechanisms.
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Affiliation(s)
- Burçak Otlu
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, 92093, USA
- Department of Bioengineering, UC San Diego, La Jolla, CA, 92093, USA
- Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA
- Department of Health Informatics, Graduate School of Informatics, Middle East Technical University, Ankara, 06800, Turkey
| | - Ludmil B Alexandrov
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, 92093, USA.
- Department of Bioengineering, UC San Diego, La Jolla, CA, 92093, USA.
- Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA.
- Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, 92037, USA.
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5
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Liu Y, Zhu J, Jin Y, Sun Z, Wu X, Zhou H, Yang Y. Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation. Nat Commun 2025; 16:3583. [PMID: 40234449 PMCID: PMC12000370 DOI: 10.1038/s41467-025-58809-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 04/03/2025] [Indexed: 04/17/2025] Open
Abstract
Disruption of bile acid (BA) metabolism causes various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains elusive. Here, we report that BA metabolism is directly controlled by a repressor function of YAP, which induces cholestasis by altering BA levels and composition via inhibiting the transcription activity of Fxr, a key physiological BA sensor. Elevated BA levels further activate hepatic YAP, resulting in a feedforward cycle leading to HCC. Mechanistically, Teads are found to bind Fxr in a DNA-binding-independent manner and recruit YAP to epigenetically suppress Fxr. Promoting BA excretion, or alleviating YAP repressor function by pharmacologically activating Fxr and inhibiting HDAC1, or overexpressing an Fxr target gene Bsep to promote BA exportation, alleviate cholestasis and HCC caused by YAP activation. Our results identify YAP's transcriptional repressor role in BA metabolism as a key driver of HCC and suggest its potential as a therapeutic target.
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MESH Headings
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Humans
- Bile Acids and Salts/metabolism
- YAP-Signaling Proteins
- Animals
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, Cytoplasmic and Nuclear/genetics
- Transcription Factors/metabolism
- Transcription Factors/genetics
- Mice
- Adaptor Proteins, Signal Transducing/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Male
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- Cell Line, Tumor
- Cell Cycle Proteins/metabolism
- Cholestasis/metabolism
- Cholestasis/genetics
- Gene Expression Regulation, Neoplastic
- Liver/metabolism
- Liver/pathology
- Hep G2 Cells
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Affiliation(s)
- Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Juanjuan Zhu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Yu Jin
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Zhonghe Sun
- Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA
| | - Xiaolin Wu
- Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA
| | - Huiping Zhou
- Department of Microbiology & Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
- Program in Gastrointestinal Malignancies, Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
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6
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Zeng T, Liao H, Xia L, You S, Huang Y, Zhang J, Liu Y, Liu X, Xie D. Multisite long-read sequencing reveals the early contributions of somatic structural variations to HBV-related hepatocellular carcinoma tumorigenesis. Genome Res 2025; 35:671-685. [PMID: 40037842 PMCID: PMC12047258 DOI: 10.1101/gr.279617.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 01/30/2025] [Indexed: 03/06/2025]
Abstract
Somatic structural variations (SVs) represent a critical category of genomic mutations in hepatocellular carcinoma (HCC). However, the accurate identification of somatic SVs using short-read high-throughput sequencing is challenging. Here, we applied long-read nanopore sequencing and multisite sampling in a cohort of 42 samples from five patients. We found that adjacent nontumor tissue is not entirely normal, as significant somatic SV alterations were detected in these nontumor genomes. The adjacent nontumor tissue is highly similar to tumor tissue in terms of somatic SVs but differs in somatic single-nucleotide variants and copy number variations. The types of SVs in adjacent nontumor and tumor tissue are markedly different, with somatic insertions and deletions identified as early genomic events associated with HCC. Notably, hepatitis B virus (HBV) DNA integration frequently results in the generation of somatic SVs, particularly inducing interchromosomal translocations (TRAs). Although HBV DNA integration into the liver genome occurs randomly, multisite shared HBV-induced SVs are early driving events in the pathogenesis of HCC. Long-read RNA sequencing reveals that some HBV-induced SVs impact cancer-associated genes, with TRAs being capable of inducing the formation of fusion genes. These findings enhance our understanding of somatic SVs in HCC and their role in early tumorigenesis.
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Affiliation(s)
- Tianfu Zeng
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Haotian Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lin Xia
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Siyao You
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanqun Huang
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jiaxun Zhang
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yahui Liu
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xuyan Liu
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Dan Xie
- Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
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7
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Kato M, Nishino J, Nagai M, Rokutan H, Narushima D, Ono H, Hasegawa T, Imoto S, Matsui S, Tsunoda T, Shibata T. Comprehensive analysis of prognosis markers with molecular features derived from pan-cancer whole-genome sequences. Hum Genomics 2025; 19:39. [PMID: 40221813 PMCID: PMC11993945 DOI: 10.1186/s40246-025-00744-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 03/19/2025] [Indexed: 04/14/2025] Open
Abstract
Cancer prognosis markers are useful for treatment decisions; however, the omics-level landscape is not well understood across multiple cancer types. Pan-Cancer Analysis of Whole Genomes (PCAWG) provides unprecedented access to various types of molecular data, ranging from typical DNA mutations and RNA expressions to more deeply analyzed or whole-genomic features, such as HLA haplotypes and structural variations. We analyzed the PCAWG data of 13 cancer types from 1,514 patients to identify prognosis markers belonging to 17 molecular features in the survival analysis based on the Cox and Lasso regression methods. We found that germline features including HLA haplotypes, neoantigens, and the number of structural variations were associated with overall survival; however, mutational signatures were not. Measuring a few markers provided a sufficient prognostic performance evaluated by c-index for each cancer type. DNA markers demonstrated better or comparable prognostic performance compared to RNA markers in some cancer types. "Universal" markers strongly associated with overall survival across cancer types were not identified. These findings will give insights into the clinical implementation of prognosis markers.
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Affiliation(s)
- Mamoru Kato
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan.
- CREST, JST, Tokyo, Japan.
| | - Jo Nishino
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
- CREST, JST, Tokyo, Japan
| | - Momoko Nagai
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
- CREST, JST, Tokyo, Japan
| | - Hirofumi Rokutan
- Division of Cancer Genomics, Research Institute, National Cancer Center Japan, Tokyo, Japan
| | - Daichi Narushima
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
| | - Hanako Ono
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
| | - Takanori Hasegawa
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shigeyuki Matsui
- CREST, JST, Tokyo, Japan
- Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tatsuhiko Tsunoda
- CREST, JST, Tokyo, Japan
- Laboratory for Medical Science Mathematics, Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo, Japan
- Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, Research Institute, National Cancer Center Japan, Tokyo, Japan
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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8
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Ng JK, Chen Y, Akinwe TM, Heins HB, Mehinovic E, Chang Y, Gutmann DH, Gurnett CA, Payne ZL, Manuel JG, Karchin R, Turner TN. Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer. CELL GENOMICS 2025; 5:100807. [PMID: 40073865 PMCID: PMC12008811 DOI: 10.1016/j.xgen.2025.100807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 12/09/2024] [Accepted: 02/11/2025] [Indexed: 03/14/2025]
Abstract
Prior studies examining genomic variants suggest that some proteins contribute to both neurodevelopmental disorders (NDDs) and cancer. While there are several potential etiologies, here, we hypothesize that missense variation in proteins occurs in different clustering patterns, resulting in distinct phenotypic outcomes. This concept was first explored in 1D protein space and expanded using 3D protein structure models. Missense de novo variants were examined from 39,883 families with NDDs and missense somatic variants from 10,543 sequenced tumors covering five The Cancer Genome Atlas (TCGA) cancer types and two Catalog of Somatic Mutations in Cancer (COSMIC) pan-cancer aggregates of tissue types. We find 18 proteins with differential missense variation clustering in NDDs compared to cancers and 19 in cancers relative to NDDs. These proteins may be important for detailed assessments in thinking of future prognostic and therapeutic applications. We establish a framework for interpreting missense patterns in NDDs and cancer, using advances in 3D protein structure prediction.
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Affiliation(s)
- Jeffrey K Ng
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yilin Chen
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Titilope M Akinwe
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Molecular Genetics & Genomics Graduate Program, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Hillary B Heins
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Elvisa Mehinovic
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yoonhoo Chang
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Human & Statistical Genetics Graduate Program, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Christina A Gurnett
- Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Zachary L Payne
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Molecular Genetics & Genomics Graduate Program, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Juana G Manuel
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Rachel Karchin
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Computer Science, Johns Hopkins University, Baltimore, MD 21205, USA; The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
| | - Tychele N Turner
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
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9
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Ekpenyong BB, Ubi GM, Kooffreh ME, Umoyen AJ, James CS, Ettah IA, Etangetuk NA, Effiom BE, Okpechi PA, Ejue BP, Ambo OA. Tumor protein 53 gene polymorphism, demographic attributes and associated risk factors among liver cancer patients in Calabar, Nigeria. BMC Cancer 2025; 25:430. [PMID: 40065269 PMCID: PMC11892161 DOI: 10.1186/s12885-025-13803-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
Mutations in the TP53 gene had been attributed to the development of liver cancer. Hepatocellular carcinoma (HCC) and liver tumour are liver diseases having high mortality rates in several populations. There is no information on the TP53 gene polymorphism among liver diseases patients in Calabar, Nigeria. This study investigated the genetic polymorphism of TP53 among HCC and liver tumour in Calabar. This research was carried out in the University of Calabar Teaching Hospital, Calabar. Blood samples were collected from 35 clinically diagnosed hepatocellular carcinoma and 10 tumour patients and 10 healthy controls. DNA was extracted from all blood samples and Polymerase Chain Reaction (PCR) was performed using specific primers. The PCR amplicons were digested using Hae III restriction enzyme and the genotypic and allelic frequencies was determined. Demographic data among participants showed that males were 68.9% (31), females (31.1%; 14), sex ratio (2.2: 0.5), mean age was 41.51 ± 2.13 years with an odds ratio of 1.25. The distribution of participants according to marital status were 33(73.3%), 10(22.2%), and 2(4.4%) for married, single, and widowed respectively. The participants were from different extractions with varied representations of Yakurr (22.2%, 10), Efik (20%, 9), Boki (13.3%, 6), Ogoja (13.3%, 6), Annang (8.8%, 4), Ibibio (2.2%, 1) and Igbo (2.2%, 1) and respectively. Approximately, 64.7% (30) of the chronic liver diseases were from the Central and Northern part of Cross River State. The risk factors were HCV infection, HBsAg+, alcoholism, smoking, consumption of groundnuts that may have been contaminated with aflatoxin and family history of the disease. PCR product yielded 254 bp and digested PCR product showed homozygous TT mutation (27), heterozygous GT mutation (17) and homozygous GG wild type (1) in cases. The overall TP53 gene mutation frequency was 46.32% (44). The frequency of G allele, T allele, GG, GT and TT were 0.21, 0.79, 0.04, 0.33 and 0.62 respectively among cases, while GG (wild type) was only detected among controls in the study population. The genotypic and allelic frequencies conform to Hardy-Weinberg equilibrium meaning that the forces of evolution were not acting on the locus. There were significant differences in the genotypic proportions of the TP53 gene polymorphism among patients and controls. This study on the TP53 gene polymorphism will serve as baseline information on the molecular etiology of hepatocellular carcinoma and liver tumour in Cross River State.
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Affiliation(s)
- Blessing B Ekpenyong
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
- Department of Plant Science and Biotechnology, University of Cross River State, Calabar, Nigeria
| | - Godwin M Ubi
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria.
| | - M E Kooffreh
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Anthony J Umoyen
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Cecilia S James
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Ivon A Ettah
- Department of Science Laboratory Technology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Nseabasi A Etangetuk
- Department of Science Laboratory Technology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Bassey E Effiom
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
| | - Philip A Okpechi
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
| | - Bassey P Ejue
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
| | - Ogar A Ambo
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
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10
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Dhanasekaran R, Suzuki H, Lemaitre L, Kubota N, Hoshida Y. Molecular and immune landscape of hepatocellular carcinoma to guide therapeutic decision-making. Hepatology 2025; 81:1038-1057. [PMID: 37300379 PMCID: PMC10713867 DOI: 10.1097/hep.0000000000000513] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 05/12/2023] [Indexed: 06/12/2023]
Abstract
Liver cancer, primarily HCC, exhibits highly heterogeneous histological and molecular aberrations across tumors and within individual tumor nodules. Such intertumor and intratumor heterogeneities may lead to diversity in the natural history of disease progression and various clinical disparities across the patients. Recently developed multimodality, single-cell, and spatial omics profiling technologies have enabled interrogation of the intertumor/intratumor heterogeneity in the cancer cells and the tumor immune microenvironment. These features may influence the natural history and efficacy of emerging therapies targeting novel molecular and immune pathways, some of which had been deemed undruggable. Thus, comprehensive characterization of the heterogeneities at various levels may facilitate the discovery of biomarkers that enable personalized and rational treatment decisions, and optimize treatment efficacy while minimizing the risk of adverse effects. Such companion biomarkers will also refine HCC treatment algorithms across disease stages for cost-effective patient management by optimizing the allocation of limited medical resources. Despite this promise, the complexity of the intertumor/intratumor heterogeneity and ever-expanding inventory of therapeutic agents and regimens have made clinical evaluation and translation of biomarkers increasingly challenging. To address this issue, novel clinical trial designs have been proposed and incorporated into recent studies. In this review, we discuss the latest findings in the molecular and immune landscape of HCC for their potential and utility as biomarkers, the framework of evaluation and clinical application of predictive/prognostic biomarkers, and ongoing biomarker-guided therapeutic clinical trials. These new developments may revolutionize patient care and substantially impact the still dismal HCC mortality.
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Affiliation(s)
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka
| | - Lea Lemaitre
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, California
| | - Naoto Kubota
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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11
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Shi J, Zhu X, Yang JB. Advances and challenges in molecular understanding, early detection, and targeted treatment of liver cancer. World J Hepatol 2025; 17:102273. [PMID: 39871899 PMCID: PMC11736488 DOI: 10.4254/wjh.v17.i1.102273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/12/2024] [Accepted: 11/27/2024] [Indexed: 01/06/2025] Open
Abstract
In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.
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Affiliation(s)
- Ji Shi
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Xu Zhu
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Jun-Bo Yang
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, Guangdong Province, China.
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12
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Aggeletopoulou I, Pantzios S, Triantos C. Personalized Immunity: Neoantigen-Based Vaccines Revolutionizing Hepatocellular Carcinoma Treatment. Cancers (Basel) 2025; 17:376. [PMID: 39941745 PMCID: PMC11815775 DOI: 10.3390/cancers17030376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/16/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, presents significant therapeutic challenges due to its molecular complexity, late-stage diagnosis, and inherent resistance to conventional treatments. The intermediate to low mutational burden in HCC and its ability to evade the immune system through multiple mechanisms complicate the development of effective therapies. Recent advancements in immunotherapy, particularly neoantigen-based vaccines, offer a promising, personalized approach to HCC treatment. Neoantigens are tumor-specific peptides derived from somatic mutations in tumor cells. Unlike normal cellular antigens, neoantigens are foreign to the immune system, making them highly specific targets for immunotherapy. Neoantigens arise from genetic alterations such as point mutations, insertions, deletions, and gene fusions, which are expressed as neoepitopes that are not present in healthy tissues, thus evading the immune tolerance mechanisms that typically protect normal cells. Preclinical and early-phase clinical studies of neoantigen-based vaccines have shown promising results, demonstrating the ability of these vaccines to elicit robust T cell responses against HCC. The aim of the current review is to provide an in-depth exploration of the therapeutic potential of neoantigen-based vaccines in HCC, focusing on neoantigen identification, vaccine platforms, and their integration with immune checkpoint inhibitors to enhance immunogenicity. It also evaluates preclinical and clinical data on efficacy and safety while addressing challenges in clinical translation. By taking advantage of the unique antigenic profile of each patient's tumor, neoantigen-based vaccines represent a promising approach in the treatment of HCC, offering the potential for improved patient outcomes, long-term remission, and a shift towards personalized, precision medicine in liver cancer therapy.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece;
| | - Spyridon Pantzios
- Hepatogastroenterology Unit, Academic Department of Internal Medicine, General Oncology Hospital of Kifissia “Agioi Anargyroi”, National and Kapodistrian University of Athens, 14564 Athens, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece;
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13
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Huang G, Stevens R, Hucek D, Purohit T, Li S, Miao H, Trost E, Hewett G, Clegg B, Park S, Rajanayake KK, Wen B, Sun D, Cierpicki T, Grembecka J. Structure-Based Development of Novel Spiro-Piperidine ASH1L Inhibitors. J Med Chem 2025; 68:174-195. [PMID: 39680643 PMCID: PMC12013431 DOI: 10.1021/acs.jmedchem.4c01673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
The absent, small, or homeotic-like 1 (ASH1L) protein is a histone lysine methyltransferase that plays a crucial role in various cancers, including leukemia. Despite representing an attractive therapeutic target, only one class of ASH1L inhibitors was identified to date. Herein, we report development of advanced ASH1L inhibitors targeting the catalytic SET domain, which were designed to access previously unexplored binding pocket on ASH1L. Extensive medicinal chemistry combined with structure-based design led to identification of 66s (AS-254s), a highly potent and selective ASH1L inhibitor (IC50 = 94 nM), representing substantially improved inhibitory activity over previously reported compounds targeting ASH1L. Furthermore, 66s effectively blocked cell proliferation and induced apoptosis and differentiation in leukemia cells harboring MLL1 translocations. Overall, this work provides a high-quality chemical probe targeting the catalytic SET domain of ASH1L with increased inhibitory activity and cellular efficacy to study biological functions of ASH1L and potentially to develop novel anticancer therapeutics.
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Affiliation(s)
- Guang Huang
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rhiannon Stevens
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Devon Hucek
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Trupta Purohit
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shuangjiang Li
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hongzhi Miao
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Elise Trost
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Geoff Hewett
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Bradley Clegg
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - SeRa Park
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Bo Wen
- College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Duxin Sun
- College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
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14
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Yu XH, Xie Y, Yu J, Zhang KN, Guo ZB, Wang D, Li ZX, Zhang WQ, Tan YY, Zhang L, Jiang WT. Loss-of-function mutations of microRNA-142-3p promote ASH1L expression to induce immune evasion and hepatocellular carcinoma progression. World J Gastroenterol 2025; 31:101198. [PMID: 39777247 PMCID: PMC11684187 DOI: 10.3748/wjg.v31.i1.101198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 09/28/2024] [Accepted: 11/14/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has been a pervasive malignancy throughout the world with elevated mortality. Efficient therapeutic targets are beneficial to treat and predict the disease. Currently, the exact molecular mechanisms leading to the progression of HCC are still unclear. Research has shown that the microRNA-142-3p level decreases in HCC, whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues. In this paper, we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity, and the association between them. AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients. METHODS In this study, we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues, and retrospectively analyzed the prognosis of HCC patients. Furthermore, explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments, which involved the following experimental methods: Immunohistochemical staining, western blot, quantitative real-time-polymerase chain reaction, flow cytometric analysis, tumor xenografts in nude mice, etc. The statistical methods involved in this study contained t-test, one-way analysis of variance, the χ 2 test, the Kaplan-Meier approach and the log-rank test. RESULTS In this study, we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate. ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3'untranslated region. Furthermore, microRNA-142-3p promotes apoptosis and inhibits proliferation, invasion, and migration of HCC cell lines in vitro via ASH1L. For the exploration mechanism, we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1, which is potentially relevant to the immune system. CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC. Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
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Affiliation(s)
- Xing-Hui Yu
- School of Medicine, Nankai University, Tianjin 300192, China
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
| | - Yan Xie
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Jian Yu
- First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Kun-Ning Zhang
- School of Medicine, Nankai University, Tianjin 300192, China
| | - Zhou-Bo Guo
- First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Di Wang
- First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Zhao-Xian Li
- School of Medicine, Nankai University, Tianjin 300192, China
| | - Wei-Qi Zhang
- School of Medicine, Nankai University, Tianjin 300192, China
| | - Yu-Ying Tan
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
| | - Li Zhang
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
| | - Wen-Tao Jiang
- School of Medicine, Nankai University, Tianjin 300192, China
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, China
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15
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Elkhadragy L, Carlino MJ, Jordan LR, Pennix T, Ismail N, Guzman G, Samuelson JP, Schook LB, Schachtschneider KM, Gaba RC. Development of a genetically tailored implantation hepatocellular carcinoma model in Oncopigs by somatic cell CRISPR editing. Dis Model Mech 2025; 18:dmm052079. [PMID: 39780710 PMCID: PMC11810043 DOI: 10.1242/dmm.052079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis, necessitating preclinical models for evaluating novel therapies. Large-animal models are particularly valuable for assessing locoregional therapies, which are widely employed across HCC stages. This study aimed to develop a large-animal HCC model with tailored tumor mutations. The Oncopig, a genetically engineered pig with inducible TP53R167H and KRASG12D, was used in the study. Hepatocytes were isolated from Oncopigs and exposed to Cre recombinase in vitro to create HCC cells, and additional mutations were introduced by CRISPR/Cas9 knockout of PTEN and CDKN2A. These edits increased Oncopig HCC cell proliferation and migration. Autologous HCC cells with these CRISPR edits were implanted into Oncopigs using two approaches: ultrasound-guided percutaneous liver injections, which resulted in the development of localized intrahepatic masses, and portal vein injections, which led to multifocal tumors that regressed over time. Tumors developed by both approaches harbored PTEN and CDKN2A knockout mutations. This study demonstrates the feasibility of developing genetically tailored HCC tumors in Oncopigs using somatic cell CRISPR editing and autologous implantation, providing a valuable large-animal model for in vivo therapeutic assessment.
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Affiliation(s)
- Lobna Elkhadragy
- Department of Radiology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | | | - Luke R. Jordan
- Department of Radiology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Thomas Pennix
- Department of Radiology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Nahed Ismail
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Jonathan P. Samuelson
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL 61802, USA
| | - Lawrence B. Schook
- Department of Radiology, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA
| | | | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
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16
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Zhang G, Xiang M, Gu L, Zhou J, Zhang B, Tian W, Deng D. The essential role of TTC28 in maintaining chromosomal stability via HSPA8 chaperone-mediated autophagy. Proc Natl Acad Sci U S A 2024; 121:e2409447121. [PMID: 39630868 DOI: 10.1073/pnas.2409447121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 10/18/2024] [Indexed: 12/07/2024] Open
Abstract
There are three distinct forms of autophagy, namely, macroautophagy, microautophagy, and HSPA8 chaperone-mediated autophagy (CMA). While macroautophagy is widely recognized as a regulator of chromosomal instability (CIN) through various pathways, the contributions of CMA and microautophagy to CIN remain uncertain. TTC28, a conserved gene in vertebrates, is frequently mutated and down-regulated in numerous human cancers. This study presents findings demonstrating the interaction between human tetratricopeptide repeat domain 28 (TTC28) and heat shock protein member 8 (HSPA8) and lysosomal-associated membrane protein 2A proteins. The tetratricopeptide repeat domains of TTC28 bind to the C-terminal motif (PTIEEVD) in HSPA8, resulting in the subsequent degradation of TTC28 via CMA/microautophagy. Notably, the baseline frequency of micronuclei (FMN) in human cancer cells with TTC28 knockout cells was three times greater than that in cells with wild-type TTC28 (7.7% vs. 2.3%, P = 4.86E-09). Furthermore, the overexpression of Ttc28 mitigated the impact of TTC28 knockout on FMN (11.9% vs. 4.8%, P = 2.83E-11). Our findings also demonstrate that CMA has a protective effect on genome stability and that TTC28 plays an essential role in the effect of CMA. These results were further supported by the quantification of γH2AX and comet analyses and the analysis of The Cancer Genome Atlas data via bioinformatics. Mechanistically, TTC28 regulates mitosis and cytokinesis, which are involved in the maintenance of genome integrity by CMA. In conclusion, our study demonstrated that TTC28 is not only an HSPA8-mediated CMA/microautophagy substrate but also essential for maintaining chromosomal stability via CMA. Comprehensive TTC28 downregulation may lead to CIN in cancer cells.
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Affiliation(s)
- Ge Zhang
- Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Meiyi Xiang
- Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Liankun Gu
- Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jing Zhou
- Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Baozhen Zhang
- Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Wei Tian
- Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Dajun Deng
- Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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17
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Li S, Lin Y, Gao X, Zeng D, Cen W, Su Y, Su J, Zeng C, Huang Z, Zeng H, Huang S, Tang M, Li X, Luo M, Huang Z, Liang R, Ye J. Integrative multi-omics analysis reveals a novel subtype of hepatocellular carcinoma with biological and clinical relevance. Front Immunol 2024; 15:1517312. [PMID: 39712016 PMCID: PMC11659151 DOI: 10.3389/fimmu.2024.1517312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 11/18/2024] [Indexed: 12/24/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and the development of accurate predictive models for prognosis and drug sensitivity remains challenging. Methods We integrated laboratory data and public cohorts to conduct a multi-omics analysis of HCC, which included bulk RNA sequencing, proteomic analysis, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics sequencing (ST-seq), and genome sequencing. We constructed a tumor purity (TP) and tumor microenvironment (TME) prognostic risk model. Proteomic analysis validated the TP-TME-related signatures. Joint analysis of scRNA-seq and ST-seq revealed characteristic clusters associated with TP high-risk subtypes, and immunohistochemistry confirmed the expression of key genes. We conducted functional enrichment analysis, transcription factor activity inference, cell-cell interaction, drug efficacy analysis, and mutation information analysis to identify a novel subtype of HCC. Results Our analyses constructed a robust HCC prognostic risk prediction model. The patients with TP-TME high-risk subtypes predominantly exhibit hypoxia and activation of the Wnt/beta-catenin, Notch, and TGF-beta signaling pathways. Furthermore, we identified a novel subtype, XPO1+Epithelial. This subtype expresses signatures of the TP risk subtype and aligns with the biological behavior of high-risk patients. Additional analyses revealed that XPO1+Epithelial is influenced primarily by fibroblasts via ligand-receptor interactions, such as FN1-(ITGAV+ITGB1), and constitute a significant component of the TP-TME subtype. Moreover, XPO1+Epithelial interact with monocytes/macrophages, T/NK cells, and endothelial cells through ligand-receptor pairs, including MIF-(CD74+CXCR4), MIF-(CD74+CD44), and VEGFA-VEGFR1R2, respectively, thereby promoting the recruitment of immune-suppressive cells and angiogenesis. The ST-seq cohort treated with Tyrosine Kinase Inhibitors (TKIs) and Programmed Cell Death Protein 1 (PD-1) presented elevated levels of TP and TME risk subtype signature genes, as well as XPO1+Epithelial, T-cell, and endothelial cell infiltration in the treatment response group. Drug sensitivity analyses indicated that TP-TME high-risk subtypes, including sorafenib and pembrolizumab, were associated with sensitivity to multiple drugs. Further exploratory analyses revealed that CTLA4, PDCD1, and the cancer antigens MSLN, MUC1, EPCAM, and PROM1 presented significantly increase expression levels in the high-risk subtype group. Conclusions This study constructed a robust prognostic model for HCC and identified novel subgroups at the single-cell level, potentially assisting in the assessment of prognostic risk for HCC patients and facilitating personalized drug therapy.
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Affiliation(s)
- Shizhou Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Xing Gao
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Dandan Zeng
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Weijie Cen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Yuejiao Su
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Jingting Su
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Can Zeng
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Zhenbo Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Haoyu Zeng
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Shilin Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Minchao Tang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Xiaoqing Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Min Luo
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Zhihu Huang
- Department of Clinical Laboratory, Minzu Hospital Guangxi Zhuang Autonomous Region, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, Guangxi, ;China
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China
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18
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Du Y, Wu S, Xi S, Xu W, Sun L, Yan J, Gao H, Wang Y, Zheng J, Wang F, Yang H, Xie D, Chen X, Ou X, Guan X, Li Y. ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404756. [PMID: 39377228 PMCID: PMC11615825 DOI: 10.1002/advs.202404756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 09/06/2024] [Indexed: 10/09/2024]
Abstract
Hepatocellular carcinoma (HCC) often occurs in the context of fibrosis or cirrhosis. Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis-associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional Ash1l depletion in the hepatocyte cell lineage (Ash1lflox/floxAlbcre) or HSCs (Ash1lflox/floxGFAPcreERT2) are generated, and these mice are challenged in a diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced model of liver fibrosis and HCC. Depleting Ash1l in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single-cell transcriptomic sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L-mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2-like pro-tumorigenic macrophages. The M2-like macrophages further enhance tumor cell proliferation and suppress CD8+ T cell activation. AS-99, a small molecule inhibitor of ASH1L, demonstrates similar anti-fibrosis and tumor-suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small-molecule therapeutic target against fibrosis-related HCC.
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Affiliation(s)
- Yuyang Du
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Shasha Wu
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Shaoyan Xi
- Department of PathologySun Yat‐Sen University Cancer CenterGuangzhou510275China
| | - Wei Xu
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and DiseasesGuangzhou Medical UniversityGuangzhou511436China
| | - Liangzhan Sun
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
- Department of Clinical OncologyThe University of Hong KongHong Kong999077China
- Institute of Cancer ResearchShenzhen Bay LaboratoryShenzhen518067China
| | - Jingsong Yan
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Han Gao
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Yanchen Wang
- Shenzhen HospitalSouthern Medical UniversityShenzhen518000China
| | - Jingyi Zheng
- Shenzhen HospitalSouthern Medical UniversityShenzhen518000China
| | - Fenfen Wang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Hui Yang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Dan Xie
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510080China
| | - Xi Chen
- Department of Systems Biology, School of Life Sciences, Southern University of Science and TechnologyShenzhen518055China
| | - Xijun Ou
- School of Life SciencesSouthern University of Science and TechnologyShenzhen518055China
| | - Xin‐Yuan Guan
- Department of Clinical OncologyThe University of Hong KongHong Kong999077China
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510080China
- The University of Hong Kong‐Shenzhen HospitalShenzhen518053China
| | - Yan Li
- Shenzhen HospitalSouthern Medical UniversityShenzhen518000China
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19
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Zhou ZJ, Ye YH, Hu ZQ, Hou YR, Liu KX, Sun RQ, Wang PC, Luo CB, Li J, Zou JX, Zhou J, Fan J, Song CL, Zhou SL. Whole-exome sequencing reveals genomic landscape of intrahepatic cholangiocarcinoma and identifies SAV1 as a potential driver. Nat Commun 2024; 15:9960. [PMID: 39551842 PMCID: PMC11570600 DOI: 10.1038/s41467-024-54387-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 11/07/2024] [Indexed: 11/19/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma, with poor prognosis and limited treatment options. The genomic features of ICC in Chinese patients remain largely unknown. In this study, we perform deep whole-exome sequencing of 204 Chinese primary ICCs and characterize genomic alterations and clonal evolution, and reveal their associations with patient outcomes. We identify six mutational signatures, including Signatures A and F, which are highly similar to previously described signatures linked to aristolochic acid and aflatoxin exposures, respectively. We also identify 13 significantly mutated genes in the ICC samples, including SAV1. We find that SAV1 was mutated in 2.9% (20/672) of 672 ICC samples. SAV1 mutation is associated with lower SAV1 protein levels, higher rates of tumor recurrence, and shorter overall patient survival. Biofunctional investigations reveal a tumor-suppressor role of SAV1: its inactivation suppresses Hippo signaling, leading to YAP activation, thereby promoting tumor growth and metastasis. Collectively, our results delineate the genomic landscape of Chinese ICCs and identify SAV1 as a potential driver of ICC.
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Affiliation(s)
- Zheng-Jun Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu-Hang Ye
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi-Qiang Hu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yue-Ru Hou
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
| | - Kai-Xuan Liu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Rong-Qi Sun
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peng-Cheng Wang
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chu-Bin Luo
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Li
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ji-Xue Zou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng-Li Song
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China.
| | - Shao-Lai Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
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20
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Vashisht V, Vashisht A, Mondal AK, Woodall J, Kolhe R. From Genomic Exploration to Personalized Treatment: Next-Generation Sequencing in Oncology. Curr Issues Mol Biol 2024; 46:12527-12549. [PMID: 39590338 PMCID: PMC11592618 DOI: 10.3390/cimb46110744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/29/2024] [Accepted: 11/03/2024] [Indexed: 11/28/2024] Open
Abstract
Next-generation sequencing (NGS) has revolutionized personalized oncology care by providing exceptional insights into the complex genomic landscape. NGS offers comprehensive cancer profiling, which enables clinicians and researchers to better understand the molecular basis of cancer and to tailor treatment strategies accordingly. Targeted therapies based on genomic alterations identified through NGS have shown promise in improving patient outcomes across various cancer types, circumventing resistance mechanisms and enhancing treatment efficacy. Moreover, NGS facilitates the identification of predictive biomarkers and prognostic indicators, aiding in patient stratification and personalized treatment approaches. By uncovering driver mutations and actionable alterations, NGS empowers clinicians to make informed decisions regarding treatment selection and patient management. However, the full potential of NGS in personalized oncology can only be realized through bioinformatics analyses. Bioinformatics plays a crucial role in processing raw sequencing data, identifying clinically relevant variants, and interpreting complex genomic landscapes. This comprehensive review investigates the diverse NGS techniques, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and single-cell RNA sequencing (sc-RNA-Seq), elucidating their roles in understanding the complex genomic/transcriptomic landscape of cancer. Furthermore, the review explores the integration of NGS data with bioinformatics tools to facilitate personalized oncology approaches, from understanding tumor heterogeneity to identifying driver mutations and predicting therapeutic responses. Challenges and future directions in NGS-based cancer research are also discussed, underscoring the transformative impact of these technologies on cancer diagnosis, management, and treatment strategies.
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Affiliation(s)
| | | | | | | | - Ravindra Kolhe
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (V.V.); (A.V.); (A.K.M.); (J.W.)
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21
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Huang G, Cierpicki T, Grembecka J. Thioamides in medicinal chemistry and as small molecule therapeutic agents. Eur J Med Chem 2024; 277:116732. [PMID: 39106658 PMCID: PMC12009601 DOI: 10.1016/j.ejmech.2024.116732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/18/2024] [Accepted: 07/30/2024] [Indexed: 08/09/2024]
Abstract
Thioamides, which are fascinating isosteres of amides, have garnered significant attention in drug discovery and medicinal chemistry programs, spanning peptides and small molecule compounds. This review provides an overview of the various applications of thioamides in small molecule therapeutic agents targeting a range of human diseases, including cancer, microbial infections (e.g., tuberculosis, bacteria, and fungi), viral infections, neurodegenerative conditions, analgesia, and others. Particular focus is given to design strategies of biologically active thioamide-containing compounds and their biological targets, such as kinases and histone methyltransferase ASH1L. Additionally, the review discusses the impact of the thioamide moiety on key properties, including potency, target interactions, physicochemical characteristics, and pharmacokinetics profiles. We hope that this work will offer valuable insights to inspire the future development of novel bioactive thioamide-containing compounds, facilitating their effective use in combating a wide array of human diseases.
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Affiliation(s)
- Guang Huang
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
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22
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Mishima M, Takai A, Takeda H, Iguchi E, Nakano S, Fujii Y, Ueno M, Ito T, Teramura M, Eso Y, Shimizu T, Maruno T, Hidema S, Nishimori K, Marusawa H, Hatano E, Seno H. TERT upregulation promotes cell proliferation via degradation of p21 and increases carcinogenic potential. J Pathol 2024; 264:318-331. [PMID: 39329419 DOI: 10.1002/path.6351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 06/13/2024] [Accepted: 08/16/2024] [Indexed: 09/28/2024]
Abstract
Telomerase reverse transcriptase (TERT) gene aberration is detectable in >80% of cases with hepatocellular carcinoma (HCC). TERT reactivation is essential for cellular immortalization because it stabilizes telomere length, although the role of TERT in hepatocarcinogenesis remains unelucidated. To elucidate the significance of aberrant TERT expression in hepatocytes in inflammation-associated hepatocarcinogenesis, we generated Alb-Cre;TertTg mice, which overexpress TERT in the liver and examined their phenotype during chronic inflammation. Based on transcriptome data from the liver tissue of Alb-Cre;TertTg mice, we examined the role of TERT in hepatocarcinogenesis in vitro. We also evaluated the relationship between TERT and cell-cycle-related molecules, including p21, in HCC samples. The liver tumor development rate was increased by TERT overexpression during chronic inflammation, especially in the absence of p53 function. Gene set enrichment analysis of liver tissues revealed that gene sets related to TNF-NFκB signaling, cell cycle, and apoptosis were upregulated in Alb-Cre;TertTg liver. A luciferase reporter assay and immunoprecipitation revealed that TERT interacted with NFκB p65 and enhanced NFκB promoter activity. On the other hand, TERT formed protein complexes with p21, cyclin A2, and cyclin E and promoted ubiquitin-mediated degradation of p21, specifically in the G1 phase. In the clinical HCC samples, TERT was highly expressed but p21 was conversely downregulated, and TERT expression was associated with the upregulation of molecules related to the cell cycle. Taken together, the aberrant upregulation of TERT increased NFκB promoter activity and promoted cell cycle progression via p21 ubiquitination, leading to hepatocarcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Masako Mishima
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eriko Iguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shigeharu Nakano
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yosuke Fujii
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masayuki Ueno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiko Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Mari Teramura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shizu Hidema
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
| | - Katsuhiko Nishimori
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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23
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Pudjihartono M, Pudjihartono N, O'Sullivan JM, Schierding W. Melanoma-specific mutation hotspots in distal, non-coding, promoter-interacting regions implicate novel candidate driver genes. Br J Cancer 2024; 131:1644-1655. [PMID: 39367275 PMCID: PMC11555344 DOI: 10.1038/s41416-024-02870-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024] Open
Abstract
BACKGROUND To develop targeted treatments, it is crucial to identify the full spectrum of genetic drivers in melanoma, including those in non-coding regions. However, recent efforts to explore non-coding regions have primarily focused on gene-adjacent elements such as promoters and non-coding RNAs, leaving intergenic distal regulatory elements largely unexplored. METHODS We used Hi-C chromatin contact data from melanoma cells to map distal, non-coding, promoter-interacting regulatory elements genome-wide in melanoma. Using this "promoter-interaction network", alongside whole-genome sequence and gene expression data from the Pan Cancer Analysis of Whole Genomes, we developed multivariate linear regression models to identify distal somatic mutation hotspots that affect promoter activity. RESULTS We identified eight recurrently mutated hotspots that are novel, melanoma-specific, located in promoter-interacting distal regulatory elements, alter transcription factor binding motifs, and affect the expression of genes (e.g., HSPB7, CLDN1, ADCY9 and FDXR) previously implicated as tumour suppressors/oncogenes in various cancers. CONCLUSIONS Our study suggests additional non-coding drivers beyond the well-characterised TERT promoter in melanoma, offering new insights into the disruption of complex regulatory networks by non-coding mutations that may contribute to melanoma development. Furthermore, our study provides a framework for integrating multiple levels of biological data to uncover cancer-specific non-coding drivers.
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Affiliation(s)
- Michael Pudjihartono
- Liggins Institute, The University of Auckland, Auckland, New Zealand
- The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand
| | | | - Justin M O'Sullivan
- Liggins Institute, The University of Auckland, Auckland, New Zealand.
- The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand.
- Australian Parkinson's Mission, Garvan Institute of Medical Research, Sydney, NSW, Australia.
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
| | - William Schierding
- Liggins Institute, The University of Auckland, Auckland, New Zealand.
- The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand.
- Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
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24
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Batty P, Lillicrap D. Adeno-associated viral vector integration: implications for long-term efficacy and safety. J Thromb Haemost 2024; 22:2945-2960. [PMID: 39097231 DOI: 10.1016/j.jtha.2024.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/05/2024] [Accepted: 07/10/2024] [Indexed: 08/05/2024]
Abstract
Adeno-associated virus (AAV) vector gene therapy provides a promising platform for treatment of monogenic inherited disorders. Clinical studies have demonstrated long-term expression with reduction in bleeding using this approach for the treatment of hemophilia. Despite these advances, there are unknowns surrounding the natural history of recombinant AAV (rAAV) vectors and the cellular mechanisms mediating vector persistence. These unknowns underpin questions regarding long-term efficacy and safety. The predominant mechanism via which AAV is proposed to persist is in circular double-stranded extrachromosomal DNA structures (episomes) within the nucleus. Studies of wild-type AAV (WT-AAV) and rAAV have demonstrated that AAV also persists via integration into a host cell's DNA. It is important to determine whether these integration events can mediate expression or could result in any long-term safety concerns. WT-AAV infection affects a large proportion of the general population, which is thought to have no long-term sequelae. Recent studies have highlighted that this WT-AAV has been detected in cases of acute hepatitis in children and in a minority of cases of hepatocellular carcinoma. Integration following treatment using rAAV has also been reported in preclinical and clinical studies. There have been variable reports on the potential implications of integration for rAAV vectors, with data in some murine studies demonstrating recurrent integration with development of hepatocellular carcinoma. These findings have not been seen in other preclinical or clinical studies. In this review, we will summarize current understanding of the natural history of AAV (wild-type and recombinant) with a focus on genomic integration and cellular implications.
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Affiliation(s)
- Paul Batty
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
| | - David Lillicrap
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
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25
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Ingram HB, Fox AH. Unveiling the intricacies of paraspeckle formation and function. Curr Opin Cell Biol 2024; 90:102399. [PMID: 39033706 DOI: 10.1016/j.ceb.2024.102399] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/23/2024]
Abstract
Paraspeckle nuclear bodies form when the NEAT1 long noncoding RNA is transcribed and bound by multiple RNA-binding proteins. First described 20 years ago, in recent years a growing appreciation of paraspeckle dynamics has led to new understandings, in both structure and function. Structurally, paraspeckles form via distinct physico-chemical domains arising from the composition of key proteins, recruited to different parts of NEAT1. These domains interact, creating a core-shell structured paraspeckle via microphase separation. Functionally, many environmental, chemical, and mechanical triggers can alter paraspeckle abundance, with important consequences depending on the cell type, developmental stage, and trigger identity. Underpinning these insights are new tools for paraspeckle research, including screening assays, proximity-based identification tools, and RNA processing modulators. A picture is emerging of paraspeckles as gene regulatory condensates in many healthy and disease settings. Critically, however, paraspeckle functional importance is generally most apparent when cells and organisms face external stressors.
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Affiliation(s)
- Hayley B Ingram
- School of Human Sciences, University of Western Australia, Crawley, Western Australia 6009, Australia
| | - Archa H Fox
- School of Human Sciences, University of Western Australia, Crawley, Western Australia 6009, Australia.
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26
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Wang M, Yan X, Dong Y, Li X, Gao B. From driver genes to gene families: A computational analysis of oncogenic mutations and ubiquitination anomalies in hepatocellular carcinoma. Comput Biol Chem 2024; 112:108119. [PMID: 38852361 DOI: 10.1016/j.compbiolchem.2024.108119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/22/2024] [Accepted: 06/06/2024] [Indexed: 06/11/2024]
Abstract
Hepatocellular carcinoma (HCC) is a widespread primary liver cancer with a high fatality rate. Despite several genes with oncogenic effects in HCC have been identified, many remain undiscovered. In this study, we conducted a comprehensive computational analysis to explore the involvement of genes within the same families as known driver genes in HCC. Specifically, we expanded the concept beyond single-gene mutations to encompass gene families sharing homologous structures, integrating various omics data to comprehensively understand gene abnormalities in cancer. Our analysis identified 74 domains with an enriched mutation burden, 404 domain mutation hotspots, and 233 dysregulated driver genes. We observed that specific low-frequency somatic mutations may contribute to HCC occurrence, potentially overlooked by single-gene algorithms. Furthermore, we systematically analyzed how abnormalities in the ubiquitinated proteasome system (UPS) impact HCC, finding that abnormal genes in E3, E2, DUB families, and Degron genes often result in HCC by affecting the stability of oncogenic or tumor suppressor proteins. In conclusion, expanding the exploration of driver genes to include gene families with homologous structures emerges as a promising strategy for uncovering additional oncogenic alterations in HCC.
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Affiliation(s)
- Meng Wang
- Faculty of Environment and Life of Beijing University of Technology, Beijing 100124, China
| | - Xinyue Yan
- Faculty of Environment and Life of Beijing University of Technology, Beijing 100124, China
| | - Yanan Dong
- Faculty of Environment and Life of Beijing University of Technology, Beijing 100124, China
| | - Xiaoqin Li
- Faculty of Environment and Life of Beijing University of Technology, Beijing 100124, China.
| | - Bin Gao
- Faculty of Environment and Life of Beijing University of Technology, Beijing 100124, China
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27
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Gan L, Wang W, Jiang J, Tian K, Liu W, Cao Z. Dual role of Nrf2 signaling in hepatocellular carcinoma: promoting development, immune evasion, and therapeutic challenges. Front Immunol 2024; 15:1429836. [PMID: 39286246 PMCID: PMC11402828 DOI: 10.3389/fimmu.2024.1429836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/12/2024] [Indexed: 09/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and ranks as the third leading cause of cancer-related mortality globally. The liver performs a wide range of tasks and is the primary organ responsible for metabolizing harmful substances and foreign compounds. Oxidative stress has a crucial role in growth and improvement of hepatocellular carcinoma (HCC). Nuclear factor erythroid 2 (1)-related factor 2 (Nrf2) is an element that regulates transcription located in the cytoplasm. It controls the balance of redox reactions by stimulating the expression of many genes that depend on antioxidant response elements. Nrf2 has contrasting functions in the normal, healthy liver and HCC. In the normal liver, Nrf2 provides advantageous benefits, while in HCC it promotes harmful effects that support the growth and survival of HCC. Continuous activation of Nrf2 has been detected in HCC and promotes its advancement and aggressiveness. In addition, Activation of Nrf2 may lead to immune evasion, weakening the immune cells' ability to attack tumors and thereby promoting tumor development. Furthermore, chemoresistance in HCC, which is considered a form of stress response to chemotherapy medications, significantly impedes the effectiveness of HCC treatment. Stress management is typically accomplished by activating specific signal pathways and chemical variables. One important element in the creation of chemoresistance in HCC is nuclear factor-E2-related factor 2 (Nrf2). Nrf2 is a transcription factor that regulates the activation and production of a group of genes that encode proteins responsible for protecting cells from damage. This occurs through the Nrf2/ARE pathway, which is a crucial mechanism for combating oxidative stress within cells.
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Affiliation(s)
- Lin Gan
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Wei Wang
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Jinxiu Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Ke Tian
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Wei Liu
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Zhumin Cao
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
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28
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Nishijima A, Oda K, Hasegawa K, Koso T, Asada K, Ikeda Y, Taguchi A, Maeda D, Nagae G, Tsuji S, Tatsuno K, Uehara Y, Kurosaki A, Sato S, Tanikawa M, Sone K, Mori M, Ikemura M, Fujiwara K, Ushiku T, Osuga Y, Aburatani H. Integrated genomic/epigenomic analysis stratifies subtypes of clear cell ovarian carcinoma, highlighting their cellular origin. Sci Rep 2024; 14:18797. [PMID: 39138354 PMCID: PMC11322660 DOI: 10.1038/s41598-024-69796-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 08/08/2024] [Indexed: 08/15/2024] Open
Abstract
The cellular origin of clear cell ovarian carcinoma (CCOC), a major histological subtype of ovarian carcinoma remains elusive. Here, we explored the candidate cellular origin and identify molecular subtypes using integrated genomic/epigenomic analysis. We performed whole exome-sequencing, microarray, and DNA methylation array in 78 CCOC samples according to the original diagnosis. The findings revealed that ARID1A and/or PIK3CA mutations were mutually exclusive with DNA repair related genes, including TP53, BRCA1, and ATM. Clustering of CCOC and other ovarian carcinomas (n = 270) with normal tissues from the fallopian tube, ovarian surface epithelium, endometrial epithelium, and pelvic peritoneum mesothelium (PPM) in a methylation array showed that major CCOC subtypes (with ARID1A and/or PIK3CA mutations) were associated with the PPM-lile cluster (n = 64). This cluster was sub-divided into three clusters: (1) mismatch repair (MMR) deficient with tumor mutational burden-high (n = 2), (2) alteration of ARID1A (n = 51), and (3) ARID1A wild-type (n = 11). The remaining samples (n = 14) were subdivided into (4) ovarian surface epithelium-like (n = 11) and (5) fallopian tube-like (considered as high-grade serous histotype; n = 3). Among these, subtypes (1-3) and others (4 and 5) were found to be associated with immunoreactive signatures and epithelial-mesenchymal transition, respectively. These results contribute to the stratification of CCOC into biological subtypes.
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Affiliation(s)
- Akira Nishijima
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Katsutoshi Oda
- Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Takahiro Koso
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Kayo Asada
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Yuji Ikeda
- Department of Obstetrics and Gynecology, Nihon University, Tokyo, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Daichi Maeda
- Department of Molecular and Cellular Pathology, Kanazawa University, Ishikawa, Japan
| | - Genta Nagae
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Shingo Tsuji
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Kenji Tatsuno
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yuriko Uehara
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Akira Kurosaki
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Sho Sato
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Michihiro Tanikawa
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Kenbun Sone
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Mayuyo Mori
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Masako Ikemura
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Keiichi Fujiwara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
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Ajuwon OR, Nsole-Biteghe FA, Ndong JD, Davids LM, Ajiboye BO, Brai B, Bamisaye FA, Falode JA, Odoh IM, Adegbite KI, Adegoke BO, Ntwasa M, Lebelo SL, Ayeleso AO. Nrf2-Mediated Antioxidant Response and Drug Efflux Transporters Upregulation as Possible Mechanisms of Resistance in Photodynamic Therapy of Cancers. Onco Targets Ther 2024; 17:605-627. [PMID: 39131905 PMCID: PMC11313505 DOI: 10.2147/ott.s457749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 05/08/2024] [Indexed: 08/13/2024] Open
Abstract
Photodynamic therapy (PDT) is a groundbreaking approach involving the induction of cytotoxic reactive oxygen species (ROS) within tumors through visible light activation of photosensitizers (PS) in the presence of molecular oxygen. This innovative therapy has demonstrated success in treating various cancers. While PDT proves highly effective in most solid tumors, there are indications that certain cancers exhibit resistance, and some initially responsive cancers may develop intrinsic or acquired resistance to PDT. The molecular mechanisms underlying this resistance are not fully understood. Recent evidence suggests that, akin to other traditional cancer treatments, the activation of survival pathways, such as the KEAP1/Nrf2 signaling pathway, is emerging as an important mechanism of post-PDT resistance in many cancers. This article explores the dual role of Nrf2, highlighting evidence linking aberrant Nrf2 expression to treatment resistance across a range of cancers. Additionally, it delves into the specific role of Nrf2 in the context of photodynamic therapy for cancers, emphasizing evidence that suggests Nrf2-mediated upregulation of antioxidant responses and induction of drug efflux transporters are potential mechanisms of resistance to PDT in diverse cancer types. Therefore, understanding the specific role(s) of Nrf2 in PDT resistance may pave the way for the development of more effective cancer treatments using PDT.
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Affiliation(s)
| | | | | | | | | | - Bartholomew Brai
- Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria
| | | | - John Adeolu Falode
- Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria
| | - Ikenna Maximillian Odoh
- Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria
- Medical Center, Federal University, Oye-Ekiti, Ekiti-State, Nigeria
| | - Kabirat Iyabode Adegbite
- Department of Environmental Health Science, College of Basic Medical and Health Sciences, Fountain University, Osogbo, Osun State, Nigeria
| | | | - Monde Ntwasa
- Department of Life and Consumer Sciences, University of South Africa, Florida Park 1709, Roodeport, South Africa
| | - Sogolo Lucky Lebelo
- Department of Life and Consumer Sciences, University of South Africa, Florida Park 1709, Roodeport, South Africa
| | - Ademola Olabode Ayeleso
- Department of Life and Consumer Sciences, University of South Africa, Florida Park 1709, Roodeport, South Africa
- Biochemistry Programme, Bowen University, Iwo, Osun State, Nigeria
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30
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Xie H, Huang G, Mai H, Chen J, Na R, Jiang D. Identification of pyroptosis subtypes and prognosis model of hepatocellular carcinoma based on pyroptosis-related genes. Cancer Med 2024; 13:e70081. [PMID: 39126216 PMCID: PMC11316015 DOI: 10.1002/cam4.70081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 04/25/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Pyroptosis, a type of programmed cell death, regulates tumor cell development. However, the role of pyroptosis-related genes (PRGs) in HCC and their association with prognosis are unclear. METHODS We conducted bioinformatics analysis to identify PRGs in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) patients. Consensus clustering classified patients into different subtypes. We used LASSO regression to established a pyroptosis subtype-related score (PSRS) related to prognosis. OncoPredict identified potential pharmaceuticals based on PSRS. RESULTS We found 20 HCC-related PRGs in 335 TCGA-LIHC patients. Consensus clustering classified patients into two subtypes. Subtype I had better overall survival and higher response to anti-PD1 treatment. The prognostic model involving 20 genes predicted poorer prognosis for high-PSRS group. The model was validated in two external cohorts. OncoPredict identified 65 potential pharmaceuticals based on PSRS. CONCLUSION Our investigation revealed a correlation between pyroptosis and HCC. We established PSRS as independent risk factors for predicting prognosis. The study paves the way for using PRGs as prognostic biomarkers and exploring personalized therapy for HCC.
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Affiliation(s)
- Haisheng Xie
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver DiseasesDepartment of Infectious Diseases and Hepatology Unit, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of PathologyThe Affiliated Hospital of Youjiang Medical University for NationalitiesBaiseGuangxiChina
| | - Guanlin Huang
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver DiseasesDepartment of Infectious Diseases and Hepatology Unit, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Haoming Mai
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver DiseasesDepartment of Infectious Diseases and Hepatology Unit, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver DiseasesDepartment of Infectious Diseases and Hepatology Unit, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Rong Na
- Division of Urology, Department of Surgery, LKS Faculty of MedicineThe University of Hong KongHong KongChina
| | - De‐Ke Jiang
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver DiseasesDepartment of Infectious Diseases and Hepatology Unit, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of PathologyThe Affiliated Hospital of Youjiang Medical University for NationalitiesBaiseGuangxiChina
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31
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Akl MG, Li L, Widenmaier SB. Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, against MASLD Progression. Int J Mol Sci 2024; 25:8046. [PMID: 39125617 PMCID: PMC11312428 DOI: 10.3390/ijms25158046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Progression of metabolic dysfunction-associated steatites liver disease (MASLD) to steatohepatitis (MASH) is driven by stress-inducing lipids that promote liver inflammation and fibrosis, and MASH can lead to cirrhosis and hepatocellular carcinoma. Previously, we showed coordinated defenses regulated by transcription factors, nuclear factor erythroid 2-related factor-1 (Nrf1) and -2 (Nrf2), protect against hepatic lipid stress. Here, we investigated protective effects of hepatocyte Nrf1 and Nrf2 against MASH-linked liver fibrosis and tumorigenesis. Male and female mice with flox alleles for genes encoding Nrf1 (Nfe2l1), Nrf2 (Nfe2l2), or both were fed a MASH-inducing diet enriched with high fat, fructose, and cholesterol (HFFC) or a control diet for 24-52 weeks. During this period, hepatocyte Nrf1, Nrf2, or combined deficiency for ~7 days, ~7 weeks, and ~35 weeks was induced by administering mice hepatocyte-targeting adeno-associated virus (AAV) expressing Cre recombinase. The effects on MASH, markers of liver fibrosis and proliferation, and liver tumorigenesis were compared to control mice receiving AAV-expressing green fluorescent protein. Also, to assess the impact of Nrf1 and Nrf2 induction on liver fibrosis, HFFC diet-fed C57bl/6J mice received weekly injections of carbon tetrachloride, and from week 16 to 24, mice were treated with the Nrf2-activating drug bardoxolone, hepatocyte overexpression of human NRF1 (hNRF1), or both, and these groups were compared to control. Compared to the control diet, 24-week feeding with the HFFC diet increased bodyweight as well as liver weight, steatosis, and inflammation. It also increased hepatocyte proliferation and a marker of liver damage, p62. Hepatocyte Nrf1 and combined deficiency increased liver steatosis in control diet-fed but not HFFC diet-fed mice, and increased liver inflammation under both diet conditions. Hepatocyte Nrf1 deficiency also increased hepatocyte proliferation, whereas combined deficiency did not, and this also occurred for p62 level in control diet-fed conditions. In 52-week HFFC diet-fed mice, 35 weeks of hepatocyte Nrf1 deficiency, but not combined deficiency, resulted in more liver tumors in male mice, but not in female mice. In contrast, hepatocyte Nrf2 deficiency had no effect on any of these parameters. However, in the 15-week CCL4-exposed and 24-week HFFC diet-fed mice, Nrf2 induction with bardoxolone reduced liver steatosis, inflammation, fibrosis, and proliferation. Induction of hepatic Nrf1 activity with hNRF1 enhanced the effect of bardoxolone on steatosis and may have stimulated liver progenitor cells. Physiologic Nrf1 delays MASLD progression, Nrf2 induction alleviates MASH, and combined enhancement synergistically protects against steatosis and may facilitate liver repair.
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Affiliation(s)
| | | | - Scott B. Widenmaier
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (M.G.A.)
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32
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Wang Y, Shang P, Xu C, Dong W, Zhang X, Xia Y, Sui C, Yang C. Novel genetic alterations in liver cancer distinguish distinct clinical outcomes and combination immunotherapy responses. Front Pharmacol 2024; 15:1416295. [PMID: 38948469 PMCID: PMC11211383 DOI: 10.3389/fphar.2024.1416295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/27/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction: Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Materials and methods: Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. Results: The genomic landscape exhibited that the most commonly altered genes in HCC were TP53, FAT3, PDE4DIP, KMT2C, FAT1, and MYO18A, while TP53, FAT1, FAT3, PDE4DIP, ROS1, and GALNT11 were frequently altered in ICC; notably, KRAS (18.18% vs. 1.29%) and BAP1 (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that LDLR, MSH2, KDM5D, PDE3A, and FOXO1 were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, p < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered RB1, NOTCH3, MGA, SYNE1, and ZFHX3, as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered LATS1 was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, p < 0.01). Regarding those treated HCC patients, TMB value, altered PTPRZ1, and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but KMT2D alterations were negatively correlated with ORR. In addition, altered KMT2D and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Conclusion: Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.
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Affiliation(s)
- Yizhou Wang
- Department of Hepatic Surgery IV and Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Peipei Shang
- Department of Medical Oncology, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chang Xu
- Department of General Surgery, Biliary Tract Disease Institute, Biliary Tract Disease Center, and Cancer Center of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xiaofeng Zhang
- Department of Hepatic Surgery IV and Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery IV and Clinical Research Institute, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chengjun Sui
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Cheng Yang
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Palihati M, Saitoh N. RNA in chromatin organization and nuclear architecture. Curr Opin Genet Dev 2024; 86:102176. [PMID: 38490161 DOI: 10.1016/j.gde.2024.102176] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 02/08/2024] [Accepted: 02/11/2024] [Indexed: 03/17/2024]
Abstract
In the cell nucleus, genomic DNA is surrounded by nonmembranous nuclear bodies. This might result from specific regions of the genome being transcribed into long noncoding RNAs (lncRNAs), which tend to remain at the sites of their own transcription. The lncRNAs seed the nuclear bodies by recruiting and concentrating proteins and RNAs, which undergo liquid-liquid-phase separation, and form molecular condensates, the so-called nuclear bodies. These nuclear bodies may provide appropriate environments for gene activation or repression. Notably, lncRNAs also contribute to three-dimensional genome structure by mediating long-range chromatin interactions. In this review, we discuss the mechanisms by which lncRNAs regulate gene expression through shaping chromatin and nuclear architectures. We also explore lncRNAs' potential as a therapeutic target for cancer, because lncRNAs are often expressed in a disease-specific manner.
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Affiliation(s)
- Maierdan Palihati
- Division of Cancer Biology, The Cancer Institute of JFCR, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Noriko Saitoh
- Division of Cancer Biology, The Cancer Institute of JFCR, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
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34
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Mabe NW, Perry JA, Malone CF, Stegmaier K. Pharmacological targeting of the cancer epigenome. NATURE CANCER 2024; 5:844-865. [PMID: 38937652 PMCID: PMC11936478 DOI: 10.1038/s43018-024-00777-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 04/19/2024] [Indexed: 06/29/2024]
Abstract
Epigenetic dysregulation is increasingly appreciated as a hallmark of cancer, including disease initiation, maintenance and therapy resistance. As a result, there have been advances in the development and evaluation of epigenetic therapies for cancer, revealing substantial promise but also challenges. Three epigenetic inhibitor classes are approved in the USA, and many more are currently undergoing clinical investigation. In this Review, we discuss recent developments for each epigenetic drug class and their implications for therapy, as well as highlight new insights into the role of epigenetics in cancer.
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Affiliation(s)
- Nathaniel W Mabe
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jennifer A Perry
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Clare F Malone
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Kimberly Stegmaier
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
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35
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Tang Q, Hu G, Sang Y, Chen Y, Wei G, Zhu M, Chen M, Li S, Liu R, Peng Z. Therapeutic targeting of PLK1 in TERT promoter-mutant hepatocellular carcinoma. Clin Transl Med 2024; 14:e1703. [PMID: 38769666 PMCID: PMC11106514 DOI: 10.1002/ctm2.1703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 04/16/2024] [Accepted: 05/06/2024] [Indexed: 05/22/2024] Open
Abstract
BACKGROUND Hotspot mutations in the promoter of telomerase reverse transcriptase (TERT) gene are the most common genetic variants in hepatocellular carcinoma (HCC) and associated with poor prognosis of the disease. However, no drug was currently approved for treating TERT promoter mutation positive HCC patients. Here, we aim to explore the potential therapeutic strategy for targeting TERT promoter mutation in HCC. METHODS The Liver Cancer Model Repository database was used for screening potential drugs to selectively suppress the growth of TERT promoter mutant HCC cells. RNA-seq, CRISPR-Cas9 technology and siRNA transfection were performed for mechanistic studies. Cell counting kit-8 (CCK8) assay and the xenograft tumour models were used for cell growth detection in vitro and in vivo, respectively. Cell apoptosis and cell cycle arrest were analysed by Annexin V-FITC staining and/or propidium iodide staining. RESULTS PLK1 inhibitors were remarkably more sensitive to HCC cells harbouring TERT promoter mutation than wild-type cells in vitro and in vivo, which were diminished after TERT promoter mutation was edited to the wild-type nucleotide. Comparing the HCC cells with wild-type promoter of TERT, PLK1 inhibitors specifically downregulated Smad3 to regulate TERT for inducing apoptosis and G2/M arrest in TERT mutant HCC cells. Moreover, knockout of Smad3 counteracted the effects of PLK1 inhibitors in TERT mutant HCC cells. Finally, a cooperative effect of PLK1 and Smad3 inhibition was observed in TERT mutant cells. CONCLUSIONS PLK1 inhibition selectively suppressed the growth of TERT mutant HCC cells through Smad3, thus contributed to discover a novel therapeutic strategy to treat HCC patients harbouring TERT promoter mutations. KEY POINTS TERT promoter mutation confers sensitivity to PLK1 inhibitors in HCC. The selective growth inhibition of TERT mutant HCC cells induced by PLK1 inhibitor was mediated by Smad3. Combined inhibition of PLK1 and Smad3 showed a cooperative anti-tumor effect in TERT mutant HCC cells.
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Affiliation(s)
- Qin Tang
- Department of Radiation OncologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Guanghui Hu
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Ye Sang
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yulu Chen
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Guangyan Wei
- Department of Radiation OncologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Meiyan Zhu
- Department of Radiation OncologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Mengke Chen
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shiyong Li
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Rengyun Liu
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Zhenwei Peng
- Department of Radiation OncologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Cancer CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
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Wang M, Yan X, Dong Y, Li X, Gao B. Machine learning and multi-omics data reveal driver gene-based molecular subtypes in hepatocellular carcinoma for precision treatment. PLoS Comput Biol 2024; 20:e1012113. [PMID: 38728362 PMCID: PMC11230636 DOI: 10.1371/journal.pcbi.1012113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 07/08/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024] Open
Abstract
The heterogeneity of Hepatocellular Carcinoma (HCC) poses a barrier to effective treatment. Stratifying highly heterogeneous HCC into molecular subtypes with similar features is crucial for personalized anti-tumor therapies. Although driver genes play pivotal roles in cancer progression, their potential in HCC subtyping has been largely overlooked. This study aims to utilize driver genes to construct HCC subtype models and unravel their molecular mechanisms. Utilizing a novel computational framework, we expanded the initially identified 96 driver genes to 1192 based on mutational aspects and an additional 233 considering driver dysregulation. These genes were subsequently employed as stratification markers for further analyses. A novel multi-omics subtype classification algorithm was developed, leveraging mutation and expression data of the identified stratification genes. This algorithm successfully categorized HCC into two distinct subtypes, CLASS A and CLASS B, demonstrating significant differences in survival outcomes. Integrating multi-omics and single-cell data unveiled substantial distinctions between these subtypes regarding transcriptomics, mutations, copy number variations, and epigenomics. Moreover, our prognostic model exhibited excellent predictive performance in training and external validation cohorts. Finally, a 10-gene classification model for these subtypes identified TTK as a promising therapeutic target with robust classification capabilities. This comprehensive study provides a novel perspective on HCC stratification, offering crucial insights for a deeper understanding of its pathogenesis and the development of promising treatment strategies.
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Affiliation(s)
- Meng Wang
- Faculty of Environment and Life of Beijing University of Technology, Beijing, China
| | - Xinyue Yan
- Faculty of Environment and Life of Beijing University of Technology, Beijing, China
| | - Yanan Dong
- Faculty of Environment and Life of Beijing University of Technology, Beijing, China
| | - Xiaoqin Li
- Faculty of Environment and Life of Beijing University of Technology, Beijing, China
| | - Bin Gao
- Faculty of Environment and Life of Beijing University of Technology, Beijing, China
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Wei H, Dong C, Li X. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future. J Clin Transl Hepatol 2024; 12:389-405. [PMID: 38638377 PMCID: PMC11022065 DOI: 10.14218/jcth.2023.00462] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
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Affiliation(s)
- Hongbin Wei
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China
- Cancer Prevention and Treatment Center of Lanzhou University School of Medicine, Lanzhou, Gansu, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, Gansu, China
- Clinical Research Center for General Surgery of Gansu Province, Lanzhou, Gansu, China
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38
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Zhao J, Liu Z, Yang K, Shen S, Peng J. DNA methylation regulator-based molecular subtyping and tumor microenvironment characterization in hepatocellular carcinoma. Front Immunol 2024; 15:1333923. [PMID: 38736884 PMCID: PMC11082416 DOI: 10.3389/fimmu.2024.1333923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Backgroud Although recent studies have reported the regulation of the immune response in hepatocellular carcinoma (HCC) through DNA methylation, the comprehensive impact methylation modifications on tumor microenvironment characteristics and immunotherapy efficacy has not been fully elucidated. Methods In this research, we conducted a comprehensive assessment of the patterns of DNA methylation regulators and the profiles of the tumor microenvironment (TME) in HCC, focusing on 21 specific DNA methylation regulators. We subsequently developed a unique scoring system, a DNA methylation score (DMscore), to assess the individual DNA methylation modifications among the three distinct methylation patterns for differentially expressed genes (DEGs). Results Three distinct methylation modification patterns were identified with distinct TME infiltration characteristics. We demonstrated that the DMscore could predict patient subtype, TME infiltration, and patient prognosis. A low DMscore, characterized by an elevated tumor mutation burden (TMB), hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, and immune activation, indicates an inflamed tumor microenvironment phenotype with a 5-year survival rate of 7.8%. Moreover, a low DMscore appeared to increase the efficacy of immunotherapy in the anti-CTLA-4/PD-1/PD-L1 cohort. Conclusions In brief, this research has enhanced our understanding of the correlation between modifications in DNA methylation patterns and the profile of the tumor microenvironment in individuals diagnosed with HCC. The DMscore may serve as an alternative biomarker for survival and efficacy of immunotherapy in patients with HCC.
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Affiliation(s)
- Junsheng Zhao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengtao Liu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Keda Yang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Sijia Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Chen F, Xiao M, Hu S, Wang M. Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer. Front Oncol 2024; 14:1381467. [PMID: 38634043 PMCID: PMC11021590 DOI: 10.3389/fonc.2024.1381467] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024] Open
Abstract
The Keap1-Nrf2 signaling pathway is a major regulator of the cytoprotective response, participating in endogenous and exogenous stress caused by ROS (reactive oxygen species). Nrf2 is the core of this pathway. We summarized the literature on Keap1-Nrf2 signaling pathway and summarized the following three aspects: structure, function pathway, and cancer and clinical application status. This signaling pathway is similar to a double-edged sword: on the one hand, Nrf2 activity can protect cells from oxidative and electrophilic stress; on the other hand, increasing Nrf2 activity can enhance the survival and proliferation of cancer cells. Notably, oxidative stress is also considered a marker of cancer in humans. Keap1-Nrf2 signaling pathway, as a typical antioxidant stress pathway, is abnormal in a variety of human malignant tumor diseases (such as lung cancer, liver cancer, and thyroid cancer). In recent years, research on the Keap1-Nrf2 signaling pathway has become increasingly in-depth and detailed. Therefore, it is of great significance for cancer prevention and treatment to explore the molecular mechanism of the occurrence and development of this pathway.
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Affiliation(s)
- Feilong Chen
- Sports Medicine Key Laboratory of Sichuan Province, Expert Centre of Sichuan Province, Institute of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Mei Xiao
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Shaofan Hu
- Department of Biochemistry and Molecular Biology, Third Military Medical University (Army Medical University), Chongqing, China
| | - Meng Wang
- Department of Biochemistry and Molecular Biology, Third Military Medical University (Army Medical University), Chongqing, China
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40
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Wang JH, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Signal Transduct Target Ther 2024; 9:78. [PMID: 38565561 PMCID: PMC10987683 DOI: 10.1038/s41392-024-01780-w] [Citation(s) in RCA: 180] [Impact Index Per Article: 180.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 02/08/2024] [Accepted: 02/19/2024] [Indexed: 04/04/2024] Open
Abstract
Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.
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Affiliation(s)
- Jiang-Hui Wang
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, 3002, Australia
| | - Dominic J Gessler
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Neurological Surgery, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Wei Zhan
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Thomas L Gallagher
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
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Ladd AD, Duarte S, Sahin I, Zarrinpar A. Mechanisms of drug resistance in HCC. Hepatology 2024; 79:926-940. [PMID: 36680397 DOI: 10.1097/hep.0000000000000237] [Citation(s) in RCA: 82] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/21/2022] [Indexed: 01/22/2023]
Abstract
HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.
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Affiliation(s)
- Alexandra D Ladd
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Sergio Duarte
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ilyas Sahin
- Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
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Chen L, Zhang C, Xue R, Liu M, Bai J, Bao J, Wang Y, Jiang N, Li Z, Wang W, Wang R, Zheng B, Yang A, Hu J, Liu K, Shen S, Zhang Y, Bai M, Wang Y, Zhu Y, Yang S, Gao Q, Gu J, Gao D, Wang XW, Nakagawa H, Zhang N, Wu L, Rozen SG, Bai F, Wang H. Deep whole-genome analysis of 494 hepatocellular carcinomas. Nature 2024; 627:586-593. [PMID: 38355797 DOI: 10.1038/s41586-024-07054-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 01/10/2024] [Indexed: 02/16/2024]
Abstract
Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China1-3. However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited4-8, with current analyses of HCC mainly from non-HBV-enriched populations9,10. Here we initiated the Chinese Liver Cancer Atlas (CLCA) project and performed deep whole-genome sequencing (average depth, 120×) of 494 HCC tumours. We identified 6 coding and 28 non-coding previously undescribed driver candidates. Five previously undescribed mutational signatures were found, including aristolochic-acid-associated indel and doublet base signatures, and a single-base-substitution signature that we termed SBS_H8. Pentanucleotide context analysis and experimental validation confirmed that SBS_H8 was distinct to the aristolochic-acid-associated SBS22. Notably, HBV integrations could take the form of extrachromosomal circular DNA, resulting in elevated copy numbers and gene expression. Our high-depth data also enabled us to characterize subclonal clustered alterations, including chromothripsis, chromoplexy and kataegis, suggesting that these catastrophic events could also occur in late stages of hepatocarcinogenesis. Pathway analysis of all classes of alterations further linked non-coding mutations to dysregulation of liver metabolism. Finally, we performed in vitro and in vivo assays to show that fibrinogen alpha chain (FGA), determined as both a candidate coding and non-coding driver, regulates HCC progression and metastasis. Our CLCA study depicts a detailed genomic landscape and evolutionary history of HCC in Chinese individuals, providing important clinical implications.
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Affiliation(s)
- Lei Chen
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
| | - Chong Zhang
- Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, China
| | - Ruidong Xue
- Peking University-Yunnan Baiyao International Medical Research Center, International Cancer Institute, Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Translational Cancer Research Center, Peking University First Hospital, Beijing, China
| | - Mo Liu
- Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Jian Bai
- Berry Oncology Corporation, Beijing, China
| | - Jinxia Bao
- Model Animal Research Center, Medical School, Nanjing University, Nanjing, China
| | - Yin Wang
- Berry Oncology Corporation, Beijing, China
| | - Nanhai Jiang
- Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Zhixuan Li
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Wenwen Wang
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ruiru Wang
- Berry Oncology Corporation, Beijing, China
| | - Bo Zheng
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | | | - Ji Hu
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ke Liu
- Berry Oncology Corporation, Beijing, China
| | - Siyun Shen
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yangqianwen Zhang
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Mixue Bai
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yan Wang
- Berry Oncology Corporation, Beijing, China
| | - Yanjing Zhu
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Shuai Yang
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jin Gu
- MOE Key Laboratory for Bioinformatics, Department of Automation, Tsinghua University, Beijing, China
| | - Dong Gao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, CAS, Shanghai, China
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Hidewaki Nakagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Ning Zhang
- Peking University-Yunnan Baiyao International Medical Research Center, International Cancer Institute, Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Translational Cancer Research Center, Peking University First Hospital, Beijing, China
| | - Lin Wu
- Berry Oncology Corporation, Beijing, China.
| | - Steven G Rozen
- Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
| | - Fan Bai
- Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, China.
| | - Hongyang Wang
- National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
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Zhu Y, Tang S, Yuan Q, Fu J, He J, Liu Z, Zhao X, Li Y, Zhao Y, Zhang Y, Zhang X, Zhang Y, Zhu Y, Wang W, Zheng B, Wu R, Wu T, Yang S, Qiu X, Shen S, Hu J, Chen L, Wang Y, Wang H, Gao D, Chen L. Integrated characterization of hepatobiliary tumor organoids provides a potential landscape of pharmacogenomic interactions. Cell Rep Med 2024; 5:101375. [PMID: 38278146 PMCID: PMC10897507 DOI: 10.1016/j.xcrm.2023.101375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 08/20/2023] [Accepted: 12/15/2023] [Indexed: 01/28/2024]
Abstract
Despite considerable efforts to identify human liver cancer genomic alterations that might unveil druggable targets, the systematic translation of multiomics data remains challenging. Here, we report success in long-term culture of 64 patient-derived hepatobiliary tumor organoids (PDHOs) from a Chinese population. A divergent response to 265 metabolism- and epigenetics-related chemicals and 36 anti-cancer drugs is observed. Integration of the whole genome, transcriptome, chromatin accessibility profiles, and drug sensitivity results of 64 clinically relevant drugs defines over 32,000 genome-drug interactions. RUNX1 promoter mutation is associated with an increase in chromatin accessibility and a concomitant gene expression increase, promoting a cluster of drugs preferentially sensitive in hepatobiliary tumors. These results not only provide an annotated PDHO biobank of human liver cancer but also suggest a systematic approach for obtaining a comprehensive understanding of the gene-regulatory network of liver cancer, advancing the applications of potential personalized medicine.
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Affiliation(s)
- Yanjing Zhu
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; National Center for Liver Cancer, Shanghai 200438, China
| | - Shijie Tang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Qiuyue Yuan
- CEMS, NCMIS, HCMS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China; School of Mathematics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China
| | - Jing Fu
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Juan He
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhuang Liu
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaofang Zhao
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yunguang Li
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Zhao
- Institute of Metabolism and Integrative Biology and School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Yani Zhang
- Institute of Metabolism and Integrative Biology and School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Xiaoyu Zhang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Yangqianwen Zhang
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Yiqin Zhu
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Wenwen Wang
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Bo Zheng
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Rui Wu
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Tong Wu
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Shuai Yang
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xinyao Qiu
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Siyun Shen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Ji Hu
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
| | - Luonan Chen
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 330106, China; Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong 519031, China.
| | - Yong Wang
- CEMS, NCMIS, HCMS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China; School of Mathematics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China; West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 330106, China.
| | - Hongyang Wang
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; National Center for Liver Cancer, Shanghai 200438, China; Institute of Metabolism and Integrative Biology and School of Life Sciences, Fudan University, Shanghai 200438, China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai 200438, China.
| | - Dong Gao
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Lei Chen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; National Center for Liver Cancer, Shanghai 200438, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai 200438, China.
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Yu X, Zhang H, Li J, Gu L, Cao L, Gong J, Xie P, Xu J. Construction of a prognostic prediction model in liver cancer based on genes involved in integrin cell surface interactions pathway by multi-omics screening. Front Cell Dev Biol 2024; 12:1237445. [PMID: 38374893 PMCID: PMC10875080 DOI: 10.3389/fcell.2024.1237445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 01/23/2024] [Indexed: 02/21/2024] Open
Abstract
Background: Liver cancer is a common malignant tumor with an increasing incidence in recent years. We aimed to develop a model by integrating clinical information and multi-omics profiles of genes to predict survival of patients with liver cancer. Methods: The multi-omics data were integrated to identify liver cancer survival-associated signal pathways. Then, a prognostic risk score model was established based on key genes in a specific pathway, followed by the analysis of the relationship between the risk score and clinical features as well as molecular and immunologic characterization of the key genes included in the prediction model. The function experiments were performed to further elucidate the undergoing molecular mechanism. Results: Totally, 4 pathways associated with liver cancer patients' survival were identified. In the pathway of integrin cell surface interactions, low expression of COMP and SPP1, and low CNVs level of COL4A2 and ITGAV were significantly related to prognosis. Based on above 4 genes, the risk score model for prognosis was established. Risk score, ITGAV and SPP1 were the most significantly positively related to activated dendritic cell. COL4A2 and COMP were the most significantly positively associated with Type 1 T helper cell and regulatory T cell, respectively. The nomogram (involved T stage and risk score) may better predict short-term survival. The cell assay showed that overexpression of ITGAV promoted tumorigenesis. Conclusion: The risk score model constructed with four genes (COMP, SPP1, COL4A2, and ITGAV) may be used to predict survival in liver cancer patients.
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Affiliation(s)
- Xiang Yu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Hao Zhang
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jinze Li
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lu Gu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lei Cao
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jun Gong
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ping Xie
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jian Xu
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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45
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Okawa Y, Sasagawa S, Kato H, Johnson TA, Nagaoka K, Kobayashi Y, Hayashi A, Shibayama T, Maejima K, Tanaka H, Miyano S, Shibahara J, Nishizuka S, Hirano S, Seto Y, Iwaya T, Kakimi K, Yasuda T, Nakagawa H. Immuno-genomic analysis reveals eosinophilic feature and favorable prognosis of female non-smoking esophageal squamous cell carcinomas. Cancer Lett 2024; 581:216499. [PMID: 38013050 DOI: 10.1016/j.canlet.2023.216499] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/13/2023] [Accepted: 11/16/2023] [Indexed: 11/29/2023]
Abstract
Most of esophageal squamous cell carcinoma (ESCC) develop in smoking males in Japan, but the genomic etiology and immunological characteristics of rare non-smoking female ECSS remain unclear. To elucidate the genomic and immunological features of ESCC in non-smoking females, we analyzed whole-genome or transcriptome sequencing data from 94 ESCCs, including 20 rare non-smoking female cases. In addition, 31,611 immune cells were extracted from four ESCC tissues and subject to single-cell RNA-seq. We compared their immuno-genomic and microbiome profiles between non-smoking female and smoking ESCCs. Non-smoking females showed much better prognosis. Whole-genome sequencing analysis showed no significant differences in driver genes or copy number alterations depending on smoking status. The mutational signatures specifically observed in non-smoking females ESCC could be attributed to aging. Immune profiling from RNA-seq revealed that ESCC in non-smoking females had high tumor microenvironment signatures and a high abundance of eosinophils with a favorable prognosis. Single-cell RNA-sequencing of intratumor immune cells revealed gender differences of eosinophils and their activation in female cases. ESCCs in non-smoking females have age-related mutational signatures and gender-specific tumor immune environment with eosinophils, which is likely to contribute to their favorable prognosis.
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Affiliation(s)
- Yuki Okawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Shota Sasagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroaki Kato
- Department of Surgery, Graduate School of Medicine, Kindai University, Osaka, Japan
| | - Todd A Johnson
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Koji Nagaoka
- Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan
| | - Yukari Kobayashi
- Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan
| | - Akimasa Hayashi
- Department of Pathology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Takahiro Shibayama
- Department of Pathology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Kazuhiro Maejima
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroko Tanaka
- M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Satoru Miyano
- M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Junji Shibahara
- Department of Pathology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Satoshi Nishizuka
- Division of Biomedical Research and Development, Iwate Medical University Institute for Biomedical Sciences, Yahaba, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Yasuyuki Seto
- Department of GI Surgery, Graduate of School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeshi Iwaya
- Department of Clinical Oncology, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Kazuhiro Kakimi
- Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan; Department of Immunology, Graduate School of Medicine, Kindai University, Osaka, Japan
| | - Takushi Yasuda
- Department of Surgery, Graduate School of Medicine, Kindai University, Osaka, Japan
| | - Hidewaki Nakagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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46
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Otlu B, Alexandrov LB. Evaluating topography of mutational signatures with SigProfilerTopography. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.08.574683. [PMID: 38260507 PMCID: PMC10802511 DOI: 10.1101/2024.01.08.574683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
The mutations found in a cancer genome are shaped by diverse processes, each displaying a characteristic mutational signature that may be influenced by the genome's architecture. While prior analyses have evaluated the effect of topographical genomic features on mutational signatures, there has been no computational tool that can comprehensively examine this interplay. Here, we present SigProfilerTopography, a Python package that allows evaluating the effect of chromatin organization, histone modifications, transcription factor binding, DNA replication, and DNA transcription on the activities of different mutational processes. SigProfilerTopography elucidates the unique topographical characteristics of mutational signatures, unveiling their underlying biological and molecular mechanisms.
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Affiliation(s)
- Burçak Otlu
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, 92093, USA
- Department of Bioengineering, UC San Diego, La Jolla, CA, 92093, USA
- Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA
- Department of Health Informatics, Graduate School of Informatics, Middle East Technical University, 06800, Ankara, Turkey
| | - Ludmil B. Alexandrov
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, 92093, USA
- Department of Bioengineering, UC San Diego, La Jolla, CA, 92093, USA
- Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA
- Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA 92037
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47
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Sun Y, Wu P, Zhang Z, Wang Z, Zhou K, Song M, Ji Y, Zang F, Lou L, Rao K, Wang P, Gu Y, Gu J, Lu B, Chen L, Pan X, Zhao X, Peng L, Liu D, Chen X, Wu K, Lin P, Wu L, Su Y, Du M, Hou Y, Yang X, Qiu S, Shi Y, Sun H, Zhou J, Huang X, Peng DH, Zhang L, Fan J. Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma. Cancer Cell 2024; 42:135-156.e17. [PMID: 38101410 DOI: 10.1016/j.ccell.2023.11.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 09/27/2023] [Accepted: 11/21/2023] [Indexed: 12/17/2023]
Abstract
Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.
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Affiliation(s)
- Yunfan Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
| | - Pin Wu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Shenzhen 518083, China
| | - Zefan Zhang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Zejian Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Kaiqian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Minfang Song
- Research Center for Intelligent Computing Platforms, Zhejiang Lab, Hangzhou, Zhejiang 311121, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Fenglin Zang
- Department of Pathology, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Limu Lou
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Keqiang Rao
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Pengxiang Wang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yutong Gu
- Department of Orthopaedic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Jie Gu
- Department of Thoracic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Binbin Lu
- Dunwill Med-Tech, Shanghai 200032, China
| | | | - Xiuqi Pan
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Xiaojing Zhao
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Lihua Peng
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Dongbing Liu
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Xiaofang Chen
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Kui Wu
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Penghui Lin
- BGI Research, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen 518083, China
| | - Liang Wu
- BGI Research, Shenzhen 518083, China
| | - Yulin Su
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China
| | - Min Du
- Department of Pathology, Huadong Hospital, Fudan University, Shanghai 200032, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xinrong Yang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Shuangjian Qiu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yinghong Shi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Huichuan Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Xingxu Huang
- Research Center for Intelligent Computing Platforms, Zhejiang Lab, Hangzhou, Zhejiang 311121, China
| | | | - Liye Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200032, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
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48
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Ito T, Ishii T, Takeda H, Sumiyoshi S, Tomofuji K, Wakama S, Makino K, Horie H, Kumagai K, Takai A, Uebayashi EY, Ogiso S, Fukumitsu K, Haga H, Seno H, Hatano E. Comprehensive analyses of the clinicopathological features and genomic mutations of combined hepatocellular-cholangiocarcinoma. Hepatol Res 2024; 54:103-115. [PMID: 37699724 DOI: 10.1111/hepr.13965] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/14/2023]
Abstract
AIM Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that has two different tumor phenotypes in a single tumor nodule. The relationship between genetic mutations and clinicopathological features of cHCC-CCA remains to be elucidated. METHODS Whole-exome sequencing analyses were carried out in 13 primary and 2 recurrent cHCC-CCAs. The whole-exome analyses and clinicopathological information were integrated. RESULTS TP53 was the most frequently mutated gene in this cohort, followed by BAP1, IDH1/2, and NFE2L2 mutations in multiple cases. All tumors with diameters <3 cm had TP53 mutations. In contrast, six of seven tumors with diameters ≥3 cm did not have TP53 mutations, but all seven tumors had mutations in genes associated with various pathways, including Wnt, RAS/PI3K, and epigenetic modulators. In the signature analysis, the pattern of mutations shown in the TP53 mutation group tended to be more similar to HCC than the TP53 nonmutation group. Mutations in recurrent cHCC-CCA tumors were frequently identical to those in the primary tumor, suggesting that those tumors originated from identical clones of the primary cHCC-CCA tumors. Recurrent and co-occurrent HCC tumors in the same patients with cHCC-CCA had either common or different mutation patterns from the primary cHCC-CCA tumors in each case. CONCLUSIONS The study suggested that there were two subtypes of cHCC-CCA, one involving TP53 mutations in the early stage of the carcinogenic process and the other not involving such mutations. The comparison of the variants between primary and recurrent tumors suggested that cHCC-CCA was derived from an identical clone.
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Affiliation(s)
- Takashi Ito
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takamichi Ishii
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Katsuhiro Tomofuji
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Wakama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenta Makino
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Horie
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Kumagai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Satoshi Ogiso
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Fukumitsu
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Surgery, Kyoto Katsura Hospital, Kyoto, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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49
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Zhou C, Weng J, Liu S, Zhou Q, Hu Z, Yin Y, Lv P, Sun J, Li H, Yi Y, Shen Y, Ye Q, Shi Y, Dong Q, Liu C, Zhu X, Ren N. Whole-exome sequencing reveals the metastatic potential of hepatocellular carcinoma from the perspective of tumor and circulating tumor DNA. Hepatol Int 2023; 17:1461-1476. [PMID: 37217808 DOI: 10.1007/s12072-023-10540-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 04/15/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND Relapse of hepatocellular carcinoma (HCC) due to vascular invasion is common, but the genomic mechanisms remain unclear, and molecular determinants of high-risk relapse cases are lacking. We aimed to reveal the evolutionary trajectory of microvascular invasion (MVI) and develop a predictive signature for relapse in HCC. METHODS Whole-exome sequencing was performed on tumor and peritumor tissues, portal vein tumor thrombus (PVTT), and circulating tumor DNA (ctDNA) to compare the genomic profiles between 5 HCC patients with MVI and 5 patients without MVI. We conducted an integrated analysis of exome and transcriptome to develop and validate a prognostic signature in two public cohorts and one cohort from Zhongshan Hospital, Fudan University. RESULTS Shared genomic landscapes and identical clonal origins among tumor, PVTT, and ctDNA were observed in MVI ( +) HCC, suggesting that genomic changes favoring metastasis occur at the primary tumor stage and are inherited in metastatic lesions and ctDNA. There was no clonal relatedness between the primary tumor and ctDNA in MVI ( - ) HCC. HCC had dynamic mutation alterations during MVI and exhibited genetic heterogeneity between primary and metastatic tumors, which can be comprehensively reflected by ctDNA. A relapse-related gene signature named RGSHCC was developed based on the significantly mutated genes associated with MVI and shown to be a robust classifier of HCC relapse. CONCLUSIONS We characterized the genomic alterations during HCC vascular invasion and revealed a previously undescribed evolution pattern of ctDNA in HCC. A novel multiomics-based signature was developed to identify high-risk relapse populations.
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Affiliation(s)
- Chenhao Zhou
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People's Republic of China
| | - Jialei Weng
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People's Republic of China
| | - Shaoqing Liu
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People's Republic of China
| | - Qiang Zhou
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People's Republic of China
| | - Zhiqiu Hu
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People's Republic of China
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China
| | - Yirui Yin
- Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 361015, People's Republic of China
| | - Peng Lv
- Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 361015, People's Republic of China
| | - Jialei Sun
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Hui Li
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yinghao Shen
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Qinghai Ye
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yi Shi
- Biomedical Research Centre, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Qiongzhu Dong
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People's Republic of China
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China
| | - Chunxiao Liu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xiaoqiang Zhu
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, School of Medicine, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, 200001, People's Republic of China.
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, 999077, People's Republic of China.
| | - Ning Ren
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People's Republic of China.
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China.
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50
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Obuse C, Hirose T. Functional domains of nuclear long noncoding RNAs: Insights into gene regulation and intracellular architecture. Curr Opin Cell Biol 2023; 85:102250. [PMID: 37806294 DOI: 10.1016/j.ceb.2023.102250] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 08/12/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023]
Abstract
Recent functional research on long noncoding RNAs (lncRNAs) has revealed their significant regulatory roles in gene expression and intracellular architecture. Well-characterized examples of such lncRNAs include Xist and NEAT1_2, which play critical roles in heterochromatin formation of inactive X-chromosomes and paraspeckle assembly, in mammalian cells. Both lncRNAs possess modular domain structures with multiple functionally distinct domains that serve as platforms for specific RNA-binding proteins (RBPs), which dictate the function of each lncRNA. Some of these RBPs bind characteristic RNA structures, which can be targeted by small chemical compounds that modulate lncRNA function by perturbing the interaction of RBPs with the RNA structures. Therefore, RNA structures hidden in lncRNAs represent a novel and potent type of therapeutic target.
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Affiliation(s)
- Chikashi Obuse
- Graduate School of Science, Osaka University, Toyonaka 560-0043, Japan; Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita 565-0871, Japan
| | - Tetsuro Hirose
- Graduate School of Science, Osaka University, Toyonaka 560-0043, Japan; Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan; Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita 565-0871, Japan.
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