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Xie Z, Dai Z, Liu Z, Chen Y, Huang S, Liu S, Li J, Shen J. The impact of an RNA-binding protein group on regulating the RSPO-LGR4/5-ZNRF3/RNF43 module and the immune microenvironment in hepatocellular carcinoma. BMC Cancer 2025; 25:751. [PMID: 40264052 PMCID: PMC12012940 DOI: 10.1186/s12885-025-13874-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] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/06/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. RNA-binding proteins (RBPs) are potential therapeutic targets because of their role in tumor progression. This study investigated the interactions between specific HCC progression-associated RBPs (HPARBPs), namely, ILF3, PTBP1, U2AF2, NCBP2, RPS3, and SSB, in HCC and their downstream targets, as well as their impact on the immune microenvironment and their clinical value. METHODS Tissue samples from human HCC, collected from 28 patients who experienced recurrence following postoperative adjuvant therapy were examined. The mRNA levels of RBPs and their prospective targets were quantified through RNA isolation and quantitative real-time PCR. Data from two public datasets were scrutinized for both expression and clinical relevance. Through Student's t test and logistic regression, HPARBPs were identified. Enhanced cross-linking immunoprecipitation (eCLIP) experiments revealed RBP-RNA interactions in HepG2 cells. For functional enrichment, Metascape was used, whereas CIBERSORT was used to characterize the immune microenvironment. RESULTS Public database analysis confirmed widespread RBP expression abnormalities in HCC (false discovery rate < 0.00001 and fold change ≥ 1.15 or ≤ 0.85), leading to the identification of 42 HPARBPs and core modules. eCLIP data analysis revealed the specificity of downstream target genes and binding site features for core HPARBPs (signal value > 3, P value < 0.01). Four core HPARBPs may bind to RNAs of genes in the RSPO-LGR4/5-ZNRF3/RNF43 module, affecting the Wnt pathway and HCC progression. Immunoinfiltration analysis revealed changes in the HCC immune microenvironment due to altered expression of relevant genes. CONCLUSION In our study, we identified core HPARBPs that might contribute to HCC progression by binding to RNAs in the RSPO-LGR4/5-ZNRF3/RNF43 module. Changes in the expression of HPARBPs affect the HCC immune microenvironment. Our findings offer novel insights into the regulatory network of Wnt pathway-related RBPs and their potential clinical value in HCC.
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Affiliation(s)
- Zhengyao Xie
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Zhiyan Dai
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Ziyao Liu
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Yiqiang Chen
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Shuting Huang
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Siyuan Liu
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
| | - Jingjing Li
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
| | - Jie Shen
- Department of Precision Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
- Comprehensive Cancer Centre, Department of Oncology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
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Zhu L, Xu Y, Huang C, Li C, Zhang Y, Li X, Pan W, Zeng Z. IRX5 Promoted SREBP1-Mediated de Novo Fatty Acid Synthesis via HMGN4 in Hepatocellular Carcinoma. J Cell Mol Med 2025; 29:e70441. [PMID: 40208102 PMCID: PMC11984319 DOI: 10.1111/jcmm.70441] [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: 06/02/2024] [Revised: 10/24/2024] [Accepted: 02/12/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC), a prevalent malignant tumour, ranks highly in both morbidity and mortality, and its prevention and treatment need further studies. The transcription factor iroquois homeobox 5 (IRX5) plays an essential role in HCC, whereas little is known about its exact functions and underlying mechanisms in tumour metabolism reprogramming. Besides, as a transcription factor that mainly locates in nuclei, IRX5 lacks a nuclear localisation sequence, which makes uncovering the mechanism of IRX5 translocating into the nuclei of great significance. Here, we first found that both IRX5 and HCC development are highly expressed; IRX5 accelerates de novo fatty acid synthesis and promotes cancer cell proliferation and progression. Moreover, the GST pull-down combined with GC/MS experiments identified an interaction between IRX5 and high-mobility group nucleosomal binding domain 4 (HMGN4). Immunofluorescence analysis showed that IRX5 and HMGN4 colocalised within the nucleus. Coimmunoprecipitation further confirmed their direct interaction. The elevated expression of HMGN4 enhanced the nuclear transport of IRX5. Taken together, our observations suggest that HMGN4 driving IRX5 nuclear translocation promotes HCC development via de novo fatty acid synthesis reprogramming.
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Affiliation(s)
- Liying Zhu
- Center for Clinical Laboratoriesthe Affiliated Hospital of Guizhou Medical UniversityGuiyangPeople's Republic of China
- School of Basic Medical Sciences/School of Biology & EngineeringGuiyangGuizhouPeople's Republic of China
| | - Yongjie Xu
- Center for Clinical Laboratoriesthe Affiliated Hospital of Guizhou Medical UniversityGuiyangPeople's Republic of China
- School of Basic Medical Sciences/School of Biology & EngineeringGuiyangGuizhouPeople's Republic of China
- Guizhou Prenatal Diagnosis Centerthe Affiliated Hospital of Guizhou Medical UniversityGuiyangPeople's Republic of China
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease ControlMinistry of Education, Guizhou Medical UniversityGuiyangChina
| | - Changyudong Huang
- School of Basic Medical Sciences/School of Biology & EngineeringGuiyangGuizhouPeople's Republic of China
- Guizhou Prenatal Diagnosis Centerthe Affiliated Hospital of Guizhou Medical UniversityGuiyangPeople's Republic of China
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease ControlMinistry of Education, Guizhou Medical UniversityGuiyangChina
| | - Chengcheng Li
- Guizhou Prenatal Diagnosis Centerthe Affiliated Hospital of Guizhou Medical UniversityGuiyangPeople's Republic of China
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease ControlMinistry of Education, Guizhou Medical UniversityGuiyangChina
| | - Yiqiong Zhang
- School of Basic Medical Sciences/School of Biology & EngineeringGuiyangGuizhouPeople's Republic of China
- Guizhou Prenatal Diagnosis Centerthe Affiliated Hospital of Guizhou Medical UniversityGuiyangPeople's Republic of China
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease ControlMinistry of Education, Guizhou Medical UniversityGuiyangChina
| | - Xing Li
- Guizhou University of Traditional Chinese MedicineGuiyangGuizhouPeople's Republic of China
| | - Wei Pan
- School of Basic Medical Sciences/School of Biology & EngineeringGuiyangGuizhouPeople's Republic of China
- Guizhou Prenatal Diagnosis Centerthe Affiliated Hospital of Guizhou Medical UniversityGuiyangPeople's Republic of China
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease ControlMinistry of Education, Guizhou Medical UniversityGuiyangChina
| | - Zhu Zeng
- School of Basic Medical Sciences/School of Biology & EngineeringGuiyangGuizhouPeople's Republic of China
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Choi SK, Kim MJ, You JS. αKG-induced oxidative stress and mTOR inhibition as a therapeutic strategy for liver cancer. Med Oncol 2025; 42:105. [PMID: 40080333 PMCID: PMC11906577 DOI: 10.1007/s12032-025-02653-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/24/2025] [Indexed: 03/15/2025]
Abstract
Despite the availability of targeted therapies, liver cancer remains a severe health burden. The need for adjuvant therapy to improve treatment efficacy and prevent recurrence is emerging. Alpha-ketoglutarate (αKG) is an intermediate in the tricarboxylic acid cycle and a cofactor for various oxygenases. A critical role of this multifunctional metabolite has started to be revealed in physiological and pathological conditions. We found that αKG exerts various anti-tumor effects in liver cancer cells. Our kinetic transcriptome study suggested that increasing reactive oxygen species and inhibiting mTORC1 signaling underlies. Indeed, αKG treatment elevated oxidative stress and induced DNA damage, presumably caused by early downregulation of the antioxidant gene SLC7A11. Further, we validated impaired mTOR signaling and decreased cellular energy production. This unique mechanism underscores αKG's potential as a liver cancer therapy by harnessing oxidative stress and disrupting metabolic signaling. These findings could provide valuable insights into further exploration of αKG as a promising therapeutic agent in liver cancer.
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Affiliation(s)
- Sung Kyung Choi
- Department of Biochemistry, School of Medicine, Konkuk University, Chungju-Si, 27478, Chungcheongbuk-Do, Korea
| | - Myoung Jun Kim
- Department of Biochemistry, School of Medicine, Konkuk University, Chungju-Si, 27478, Chungcheongbuk-Do, Korea
| | - Jueng Soo You
- Department of Biochemistry, School of Medicine, Konkuk University, Chungju-Si, 27478, Chungcheongbuk-Do, Korea.
- Research Institute of Medical Science, KU Open Innovation Center, Chungju-Si, 27478, Chungcheongbuk-Do, Korea.
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Li J, Bai L, Xin Z, Song J, Chen H, Song X, Zhou J. TERT-TP53 mutations: a novel biomarker pair for hepatocellular carcinoma recurrence and prognosis. Sci Rep 2025; 15:3620. [PMID: 39880909 PMCID: PMC11779956 DOI: 10.1038/s41598-025-87545-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: 07/19/2024] [Accepted: 01/20/2025] [Indexed: 01/31/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, and ranks among the most lethal malignancies globally, primarily due to its high rates of recurrence and metastasis. Despite the urgency, no reliable biomarkers currently exist for predicting tumor recurrence in HCC. Telomerase reverse transcriptase (TERT) promoter mutations (TERTpm) and cellular tumor antigen p53 mutations (TP53m) have been frequently documented in HCC, but their combined clinical significance remains undefined. In this study, we investigated the clinical implications of TERTpm, TP53m, and their co-occurrence in 50 HCC tissue samples using the next-generation sequencing (NGS) technology. We identified TERTpm (C228T) and TP53m in 16 (32%) and 24 (48%) samples, respectively. Our findings indicate that these mutations are more prevalent in male patients (100% for TERTpm, 83.33% for TP53m), in those with solitary tumors (87.5% for both), in individuals with G2-G3 hepatitis (100% / 83.3%), and in cases of moderately differentiated tumors (75.0% / 83.3%). Furthermore, patients with both TERTpm and TP53m exhibited a significantly higher risk of tumor relapse (P < 0.05) and shorter progression-free survival (P < 0.05). Collectively, our results suggest that presence of both TERTpm and TP53m may serve as a robust predictor of tumor recurrence and a marker of poor prognosis in HCC.
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Affiliation(s)
- Jin Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Med + Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Ling Bai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Med + Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Zhaodan Xin
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Med + Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Jiajia Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Med + Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Hao Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Med + Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China
| | - Xingbo Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
- Med + Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China.
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
- Med + Molecular Diagnostics Institute of West China Hospital/West China School of Medicine, Chengdu, China.
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Hui Y, Leng J, Jin D, Wang G, Liu K, Bu Y, Wang Q. BRG1 promotes liver cancer cell proliferation and metastasis by enhancing mitochondrial function and ATP5A1 synthesis through TOMM40. Cancer Biol Ther 2024; 25:2375440. [PMID: 38978225 PMCID: PMC11236295 DOI: 10.1080/15384047.2024.2375440] [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: 02/16/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.
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Affiliation(s)
- Yongfeng Hui
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Hepatobiliary Surgery, Ningxia Hepatobiliary and Pancreatic Surgical Diseases Clinical Medical Research Center, Yinchuan, Ningxia, China
| | - Junzhi Leng
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Hepatobiliary Surgery, Ningxia Hepatobiliary and Pancreatic Surgical Diseases Clinical Medical Research Center, Yinchuan, Ningxia, China
| | - Dong Jin
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Hepatobiliary Surgery, Ningxia Hepatobiliary and Pancreatic Surgical Diseases Clinical Medical Research Center, Yinchuan, Ningxia, China
| | - Genwang Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Hepatobiliary Surgery, Ningxia Hepatobiliary and Pancreatic Surgical Diseases Clinical Medical Research Center, Yinchuan, Ningxia, China
| | - Kejun Liu
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Hepatobiliary Surgery, Ningxia Hepatobiliary and Pancreatic Surgical Diseases Clinical Medical Research Center, Yinchuan, Ningxia, China
| | - Yang Bu
- Department of Hepatobiliary Surgery, Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Hepatobiliary Surgery, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Qi Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Hepatobiliary Surgery, Ningxia Hepatobiliary and Pancreatic Surgical Diseases Clinical Medical Research Center, Yinchuan, Ningxia, China
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Kassem PH, Montasser IF, Mahmoud RM, Ghorab RA, AbdelHakam DA, Fathi MESA, Wahed MAA, Mohey K, Ibrahim M, Hadidi ME, Masssoud YM, Salah M, Abugable A, Bahaa M, Khamisy SE, Meteini ME. Genomic landscape of hepatocellular carcinoma in Egyptian patients by whole exome sequencing. BMC Med Genomics 2024; 17:202. [PMID: 39123171 PMCID: PMC11311965 DOI: 10.1186/s12920-024-01965-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: 02/02/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. METHODS Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. RESULTS Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. CONCLUSION Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients.
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Affiliation(s)
- Perihan Hamdy Kassem
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Iman Fawzy Montasser
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Ramy Mohamed Mahmoud
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Rasha Ahmed Ghorab
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Dina A AbdelHakam
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Marwa A Abdel Wahed
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Khaled Mohey
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mariam Ibrahim
- Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed El Hadidi
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham Dubai Campus, Dubai, United Arab Emirates
- Bioinformatics Group, Center for Informatics Science(CIS), School of Information Technology and Computer Science(ITCS), Nile University, Giza, Egypt
| | - Yasmine M Masssoud
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Manar Salah
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Arwa Abugable
- School of Biosciences, University of Sheffield, Sheffield, UK
| | - Mohamad Bahaa
- Hepato-Pancreatico-Biliary Surgery Department and liver Transplantation, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Mahmoud El Meteini
- Hepato-Pancreatico-Biliary Surgery Department and liver Transplantation, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Ferreira-Silva GÁ, Rodrigues DA, Pressete CG, Caixeta ES, Gamero AMC, Miyazawa M, Hanemann JAC, Fraga CAM, Aissa AF, Ionta M. Selective inhibition of HDAC6 by N-acylhydrazone derivative reduces the proliferation and induces senescence in carcinoma hepatocellular cells. Toxicol In Vitro 2024; 99:105884. [PMID: 38945376 DOI: 10.1016/j.tiv.2024.105884] [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: 05/03/2024] [Revised: 06/13/2024] [Accepted: 06/25/2024] [Indexed: 07/02/2024]
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths globally. Systemic therapy is the only treatment option for HCC at an advanced stage, with limited therapeutic response. In this study, we evaluated the antitumor potential of four N-acylhydrazone (NAH) derivatives, namely LASSBio-1909, 1911, 1935, and 1936, on HCC cell lines. We have previously demonstrated that the aforementioned NAH derivatives selectively inhibit histone deacetylase 6 (HDAC6) in lung cancer cells, but their effects on HCC cells have not been explored. Thus, the present study aimed to evaluate the effects of NAH derivatives on the proliferative behavior of HCC cells. LASSBio-1911 was the most cytotoxic compound against HCC cells, however its effects were minimal on normal cells. Our results showed that LASSBio-1911 inhibited HDAC6 in HCC cells leading to cell cycle arrest and decreased cell proliferation. There was also an increase in the frequency of cells in mitosis onset, which was associated with disturbing mitotic spindle formation. These events were accompanied by elevated levels of CDKN1A mRNA, accumulation of CCNB1 protein, and sustained ERK1 phosphorylation. Furthermore, LASSBio-1911 induced DNA damage, resulting in senescence and/or apoptosis. Our findings indicate that selective inhibition of HDAC6 may provide an effective therapeutic strategy for the treatment of advanced HCC, including tumor subtypes with integrated viral genome. Further, in vivo studies are required to validate the antitumor effect of LASSBio-1911 on liver cancer.
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Affiliation(s)
| | - Daniel Alencar Rodrigues
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, CCS, Rio de Janeiro, RJ, Brazil
| | | | | | - Angel Mauricio Castro Gamero
- Human Genetics Laboratory, Institute of Natural Science, Federal University of Alfenas, zip-code 37130-001, Alfenas, MG, Brazil
| | - Marta Miyazawa
- School of Dentistry, Federal University of Alfenas, 37130-001 MG, Brazil
| | | | - Carlos Alberto Manssour Fraga
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, CCS, Rio de Janeiro, RJ, Brazil
| | - Alexandre Ferro Aissa
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil.
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil.
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Liu S, Zang Y, Huang C, Liu Y. Downregulation of Rab23 inhibits hepatocellular carcinoma by repressing SHH signaling pathway. Cancer Rep (Hoboken) 2024; 7:e1921. [PMID: 37884351 PMCID: PMC10809273 DOI: 10.1002/cnr2.1921] [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: 03/12/2023] [Revised: 09/14/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumors and the third leading cause of cancer-related death worldwide. As an oncogene, Rab23 has been shown to be significantly related to the growth and migration of hepatocellular carcinoma in both in vitro and in vivo studies, but its underlying mechanism remains obscure. In the present study, we examined the effect of inhibiting Rab23 expression on the pathological progression of HCC. The correlation between liver Rab23 gene expression and survival probability in human HCC patients was analyzed using the TCGA database and CPTAC database. Rab23 knockdown hepatocellular carcinoma cell line was generated through lentiviral transduction, then we established a nude HCC xenograft model by subcutaneously implanting the transfected cells. The analysis of gene and protein expression was carried out using Western blot or RT-qPCR, respectively. Flow cytometry analysis was used to detect the level of apoptosis. The expression levels of key proteins involved in the Sonic Hedgehog (SHH) signaling pathway were assessed. The results showed that HCC patients with low levels of hepatic Rab23 mRNA and protein had a better survival tendency than those with higher levels of Rab23. Cell proliferations were reduced and apoptosis levels were increased after Knocking down Rab23 in HCC cell lines. Furthermore, in vivo studies have demonstrated that suppression of the Rab23 gene results in decreased tumor size, proliferation rate, and reduced levels of SHH-related proteins Smoothened and GLI-1. The above results suggest that Rab23 is involved in the pathological progression of HCC as an important regulator of the SHH signaling pathway, which also provides an important research basis for new therapeutic strategies for HCC.
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Affiliation(s)
- Si‐Jia Liu
- Department of AnesthesiologyThe Affiliated Hospital of Jiujiang UniversityJiujiangChina
| | - Yu‐Wei Zang
- Archives of Jiujiang UniversityJiujiangChina
| | - Cui‐Jun Huang
- Physical Examination CenterThe First People's Hospital of Jiujiang CityJiujiangChina
| | - Yun‐Jian Liu
- Department of Hepatobiliary SurgeryThe Affiliated Hospital of Jiujiang UniversityJiujiangChina
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Yu J, Ling S, Hong J, Zhang L, Zhou W, Yin L, Xu S, Que Q, Wu Y, Zhan Q, Bao J, Xu N, Liu Y, Chen K, Wei X, Liu Z, Feng T, Zhou L, Xie H, Wang S, Liu J, Zheng S, Xu X. TP53/mTORC1-mediated bidirectional regulation of PD-L1 modulates immune evasion in hepatocellular carcinoma. J Immunother Cancer 2023; 11:e007479. [PMID: 38030304 PMCID: PMC10689408 DOI: 10.1136/jitc-2023-007479] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Immunotherapy has facilitated great breakthroughs in the treatment of hepatocellular carcinoma (HCC). However, the efficacy and response rate of immunotherapy are limited and vary among different patients with HCC. TP53 mutation substantially affects the expression of immune checkpoint molecules in multiple cancers. However, the regulatory relationship between programmed death ligand 1 (PD-L1) and TP53 is poorly studied in HCC. We aimed to elucidate the regulatory mechanism of PD-L1 in HCC with different TP53 statuses and to assess its role in modulating immune evasion in HCC. METHODS HCC mouse models and cell lines with different TP53 statuses were constructed. PD-L1 levels were detected by PCR, western blotting and flow cytometry. RNA-seqencing, immunoprecipitation, chromatin immunoprecipitation and transmission electron microscopy were used to elucidate the regulatory mechanism in HCC with different TP53 status. HCC mouse models and patient with HCC samples were analyzed to demonstrate the preclinical and clinical significance of the findings. RESULTS We report that loss of p53 promoted PD-L1 expression and reduced CD8+ T-cell infiltration in patient with HCC samples and mouse models. Mammalian target of rapamycin (mTOR) pathway was activated in p53-loss-of-function HCC or after knocking down TP53. The transcription factor E2F1 was found to bind to the p53 protein in TP53 wild-type HCC cells, and inhibiting mammalian target of rapamycin complex 1 (mTORC1) disrupted this binding and enhanced E2F1 translocation to the nucleus, where it bound to the PD-L1 promoter and transcriptionally upregulated PD-L1. In p53-loss-of-function HCC cells, autophagosomes were activated after mTORC1 suppression, promoting the degradation of PD-L1 protein. The combination of mTOR inhibitor and anti-PD-L1 antibody enhanced CD8+ T-cell infiltration and tumor suppression in TP53 wild-type HCC mouse models, but no benefit was observed in p53-loss-of-function HCC mouse models. In patients with TP53 wild-type HCC, PD-L1 levels were significantly higher in the high E2F1 group than in the low E2F1 group, and the low E2F1 level group had significantly superior survival. CONCLUSION We revealed the bidirectional regulatory mechanism of PD-L1 mediated by TP53/mTORC1 in HCC. The combination of mTOR inhibitor and anti-PD-L1 antibody could be a novel precise immunotherapy scheme for TP53 wild-type HCC.
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Affiliation(s)
- Jiongjie Yu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Sunbin Ling
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | | | - Lincheng Zhang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Wei Zhou
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Lu Yin
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Shengjun Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Qingyang Que
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Yongfeng Wu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Qifan Zhan
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiaqi Bao
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Nan Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Yuchen Liu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kangchen Chen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Xuyong Wei
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Zhikun Liu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Tingting Feng
- Department of Colorectal Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Lin Zhou
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shuai Wang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Jimin Liu
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Shusen Zheng
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
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10
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Ru B, Hu J, Zhang N, Wan Q. A novel metabolism-related gene signature in patients with hepatocellular carcinoma. PeerJ 2023; 11:e16335. [PMID: 38025761 PMCID: PMC10640845 DOI: 10.7717/peerj.16335] [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: 06/21/2023] [Accepted: 10/02/2023] [Indexed: 12/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global challenge as it is the sixth most common neoplasm worldwide and the third leading cause of cancer-related death. A key feature of HCC is abnormal metabolism, which promotes cancer cell proliferation, survival, invasion, and metastasis. However, the significance of metabolism-related genes (MRGs) in HCC remains to be elucidated. Here, we aim to establish a novel metabolism-related prognostic signature for the prediction of patient outcomes and to investigate the value of MRG expression in the prognostic prediction of HCC. In our research, a Metabolism-Related Risk Score (MRRS) model was constructed using 14 MRGs (DLAT, SEPHS1, ACADS, UCK2, GOT2, ADH4, LDHA, ME1, TXNRD1, B4GALT2, AK2, PTDSS2, CSAD, and AMD1). The Kaplan-Meier curve confirmed that the MRRS has a high accuracy in predicting the prognosis of HCC patients (p < 0.001). According to the MRRS model, the area under the curve (AUC) values for predicting the prognosis of patients with hepatocellular carcinoma at 1, 3, and 5 years reached 0.829, 0.760, and 0.739, respectively. Functional analyses revealed that signaling pathways associated with the cell cycle were largely enriched by differential genes between high and low-risk groups. In addition, dendritic cells (DCs) (p < 0.001), CD4+ T cells (p < 0.01), CD8+ T cells (p < 0.001), B cells (p < 0.001), neutrophils (p < 0.001), macrophages (p < 0.001) had a higher proportion of infiltrates in high-risk populations. Low GOT2 expression is associated with poor prognosis in patients with hepatocellular carcinoma. Knockdown of GOT2 significantly increased the migration capacity of the Huh7 and MHCC97H hepatocellular carcinoma lines. Our research reveals that GOT2 is negatively related to the survival of patients with hepatocellular carcinoma and GOT2 may contribute to tumor progression by inhibiting the ability of tumor cells to migrate.
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Affiliation(s)
- Bin Ru
- Department of Pain Management, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Jiaqi Hu
- Department of Pain Management, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
- Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, China
| | - Nannan Zhang
- Department of Pain Management, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Quan Wan
- Department of Pain Management, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
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11
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Ozono Y, Kawakami H, Uchiyama N, Hatada H, Ogawa S. Current status and issues in genomic analysis using EUS-FNA/FNB specimens in hepatobiliary-pancreatic cancers. J Gastroenterol 2023; 58:1081-1093. [PMID: 37698719 PMCID: PMC10590314 DOI: 10.1007/s00535-023-02037-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/28/2023] [Indexed: 09/13/2023]
Abstract
Comprehensive genomic profiling based on next-generation sequencing has recently been used to provide precision medicine for various advanced cancers. Endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) and EUS-guided fine-needle biopsy (EUS-FNB) play essential roles in the diagnosis of abdominal masses, mainly pancreatic cancers. In recent years, CGP analysis using EUS-FNA/FNB specimens for hepatobiliary-pancreatic cancers has increased; however, the success rate of CGP analysis is not clinically satisfactory, and many issues need to be resolved to improve the success rate of CGP analysis. In this article, we review the transition from EUS-FNA to FNB, compare each test, and discuss the current status and issues in genomic analysis of hepatobiliary-pancreatic cancers using EUS-FNA/FNB specimens.
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Affiliation(s)
- Yoshinori Ozono
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
| | - Hiroshi Kawakami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.
| | - Naomi Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
| | - Hiroshi Hatada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
| | - Souichiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
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12
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Machado IF, Miranda RG, Dorta DJ, Rolo AP, Palmeira CM. Targeting Oxidative Stress with Polyphenols to Fight Liver Diseases. Antioxidants (Basel) 2023; 12:1212. [PMID: 37371941 DOI: 10.3390/antiox12061212] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
Reactive oxygen species (ROS) are important second messengers in many metabolic processes and signaling pathways. Disruption of the balance between ROS generation and antioxidant defenses results in the overproduction of ROS and subsequent oxidative damage to biomolecules and cellular components that disturb cellular function. Oxidative stress contributes to the initiation and progression of many liver pathologies such as ischemia-reperfusion injury (LIRI), non-alcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC). Therefore, controlling ROS production is an attractive therapeutic strategy in relation to their treatment. In recent years, increasing evidence has supported the therapeutic effects of polyphenols on liver injury via the regulation of ROS levels. In the current review, we summarize the effects of polyphenols, such as quercetin, resveratrol, and curcumin, on oxidative damage during conditions that induce liver injury, such as LIRI, NAFLD, and HCC.
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Affiliation(s)
- Ivo F Machado
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000 Coimbra, Portugal
- IIIUC-Institute of Interdisciplinary Research, University of Coimbra, 3000 Coimbra, Portugal
| | - Raul G Miranda
- School of Pharmaceutical Science of Ribeirão Preto, University of São Paulo, São Paulo 14040, Brazil
| | - Daniel J Dorta
- Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040, Brazil
| | - Anabela P Rolo
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
| | - Carlos M Palmeira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
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13
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Yao M, Wang JJ, Chen XY, Sai WL, Yang J, Wang DF, Wang L, Yao DF. Oncogenic Wnt3a is a promising sensitive biomarker for monitoring hepatocarcinogenesis. Hepatobiliary Pancreat Dis Int 2023; 22:263-269. [PMID: 36435702 DOI: 10.1016/j.hbpd.2022.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND The effective treatment for hepatocellular carcinoma (HCC) depends on early diagnosis. Previously, the abnormal expression of Wnt3a as the key signaling molecule in the Wnt/β-catenin pathway was found in HCC cells and could be released into the circulation. In this study, we used rat model of hepatocarcinogenesis to dynamically investigate the alteration of oncogenic Wnt3a and to explore its early monitor value for HCC. METHODS Sprague-Dawley rats (SD) were fed with diet 2-fluorenylacetamide (2-FAA, 0.05%) for inducing hepatocarcinogenesis, and grouped based on liver morphological alteration by Hematoxylin & Eosin (H&E) staining; rats fed with normal chow were used as normal control (NC). Total RNA and protein were purified from rat livers. Differently expressed genes (DEGs) or Wnt3a mRNA, cellular distribution, and Wnt3a protein levels were analyzed by whole genome microarray with signal logarithm ratio (SLR log2cy5/cy3), immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. RESULTS Models of rat hepatocarcinogenesis were successfully established based on liver histopathological H&E staining. Rats were divided into the cell degeneration (rDeg), precancerosis (rPre-C) and HCC (rHCC) groups. Total numbers of the up- and down-regulated DEGs with SLR ≥ 8 were 55 and 48 in the rDeg group, 268 and 57 in the rPre-C group, and 312 and 201 in the rHCC group, respectively. Significantly altered genes were involved in cell proliferation, signal transduction, tumor metastasis, and apoptosis. Compared with the NC group, Wnt3a mRNA was increased by 4.6 folds (P < 0.001) in the rDeg group, 7.4 folds (P < 0.001) in the rPre-C group, and 10.4 folds (P < 0.001) in the rHCC group; the positive rates of liver Wnt3a were 66.7% (P = 0.001) in the rDeg group, 100% (P < 0.001) in the rPre-C group, and 100% (P < 0.001) in the rHCC group, respectively. Also, there were significant differences of liver Wnt3a (P < 0.001) or serum Wnt3a (P < 0.001) among different groups. CONCLUSIONS Overexpression of Wnt3a was associated with rat hepatocarcinogenesis and it should be expected to be a promising monitoring biomarker for HCC occurrence at early stage.
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Affiliation(s)
- Min Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China; Department of Immunology, Medical School of Nantong University, Nantong 226001, China
| | - Jian-Jun Wang
- Nantong Health College of Jiangsu Province, Nantong 226016, China
| | - Xi-Yu Chen
- Department of Immunology, Medical School of Nantong University, Nantong 226001, China
| | - Wen-Li Sai
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Jie Yang
- Department of Molecular Biology, Life Science School of Nantong University, Nantong 226019, China
| | - De-Feng Wang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Li Wang
- Research Center for Intelligence Information Technology of Nantong University, Nantong 226019, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China.
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14
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Guo H, Lu F, Lu R, Huang M, Li X, Yuan J, Wang F. A novel tumor 4-driver gene signature for the prognosis of hepatocellular carcinoma. Heliyon 2023; 9:e17054. [PMID: 37484410 PMCID: PMC10361245 DOI: 10.1016/j.heliyon.2023.e17054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 07/25/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC), the main type of liver cancer, is the second most lethal tumor worldwide, with a 5-year survival rate of only 18%. Driver genes facilitate cancer cell growth and spread in the tumor microenvironment. Here, a comprehensive driver gene signature for the prognosis of HCC was developed. Methods HCC driver genes were analyzed comprehensively to develop a better prognostic signature. The dataset of HCC patients included mRNA sequencing data and clinical information from the TCGA, the ICGC, and the Guangxi Medical University Cancer Hospital cohorts. First, LASSO was performed to develop a prognostic signature for differentially expressed driver genes in the TCGA cohort. Then, the robustness of the signature was assessed using survival and time-dependent ROC curves. Furthermore, independent predictors were determined using univariate and multivariate Cox regression analyses. Stepwise multi-Cox regression analysis was employed to identify significant variables for the construction of a nomogram that predicts survival rates. Functional analysis by Spearman correlation analysis, enrichment analysis (GO, KEGG, and GSEA), and immunoassay (ssGSEA and xCell) were performed. Result A 4-driver gene signature (CLTC, DNMT3A, GMPS, and NRAS) was successfully constructed and showed excellent predictive efficiency in three cohorts. The nomogram indicated high predictive accuracy for the 1-, 3-, and 5-year prognoses of HCC patients, which included clinical information and risk score. Enrichment analysis revealed that driver genes were involved in regulating oncogenic processes, including the cell cycle and metabolic pathways, which were associated with the progression of HCC. ssGSEA and xCell showed differences in immune infiltration and the immune microenvironment between the two risk groups. Conclusion The 4-driver gene signature is closely associated with the survival prediction of HCC and is expected to provide new insights into targeted therapy for HCC patients.
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Affiliation(s)
- Houtian Guo
- First Clinical College of Guangxi Medical University, Nanning, China
| | - Fei Lu
- First Clinical College of Guangxi Medical University, Nanning, China
| | - Rongqi Lu
- First Clinical College of Guangxi Medical University, Nanning, China
| | - Meiqi Huang
- First Clinical College of Guangxi Medical University, Nanning, China
| | - Xuejing Li
- Department of Physiology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Jianhui Yuan
- Department of Physics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Feng Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
- Key Laboratory of Biological Molecular Medicine Research, Guangxi Medical University, Education Department of Guangxi Zhuang Autonomous Region, Nanning, China
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15
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Zeng ZM, Mo N, Zeng J, Ma FC, Jiang YF, Huang HS, Liao XW, Zhu GZ, Ma J, Peng T. Advances in postoperative adjuvant therapy for primary liver cancer. World J Gastrointest Oncol 2022; 14:1604-1621. [PMID: 36187393 PMCID: PMC9516643 DOI: 10.4251/wjgo.v14.i9.1604] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/13/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.
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Affiliation(s)
- Zhi-Ming Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ning Mo
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fu-Chao Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Feng Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Prognostic Value of MUC16 Mutation and Its Correlation with Immunity in Hepatocellular Carcinoma Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3478861. [PMID: 36034941 PMCID: PMC9410786 DOI: 10.1155/2022/3478861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 12/24/2022]
Abstract
Objective Identifying gene mutation signatures will enable a better understanding for the occurrence, development, and prognosis of hepatocellular carcinoma (HCC) and provide some potential biomarkers for clinical practice. This study investigated the mutated genes in HCC patients and assessed their relationship with tumor mutation burden (TMB) and prognosis. Methods The somatic mutation annotation format (MAF) document, mRNA expression matrix, and clinical information of HCC patients were obtained from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA) database. The differences of TMB between the mutant type and the wild-type genes were detected using the Mann–Whitney U test. The link of gene mutations with prognosis was explored by the Kaplan–Meier analysis. The proportion of 22 immune cells' composition was measured using CIBERSORT algorithm. Results The two databases screened 16 common mutated genes, which included TP53, TTN, LRP1B, ZFHX4, MUC16, OBSCN, CSMD3, FLG, CSMD1, SYNE1, SPTA1, USH2A, KMT2C, PCLO, HMCN1, and FAT3. After a series of analysis, MUC16 mutation was found to be highly correlated with TMB and was regarded as an independent factor predicting HCC. Furthermore, gene set enrichment analysis (GSEA) indicated that the MUC16 mutation was significantly involved in HCC cell metabolism. Conclusions MUC16 mutation seems to be a valuable potential biomarker for HCC development and its overall survival.
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Bao X, Li Q, Chen J, Chen D, Ye C, Dai X, Wang Y, Li X, Rong X, Cheng F, Jiang M, Zhu Z, Ding Y, Sun R, Liu C, Huang L, Jin Y, Li B, Lu J, Wu W, Guo Y, Fu W, Langley SR, Tano V, Fang W, Guo T, Sheng J, Zhao P, Ruan J. Molecular Subgroups of Intrahepatic Cholangiocarcinoma Discovered by Single-Cell RNA Sequencing-Assisted Multi-Omics Analysis. Cancer Immunol Res 2022; 10:811-828. [PMID: 35604302 DOI: 10.1158/2326-6066.cir-21-1101] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/07/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly aggressive tumor type that responds poorly to chemotherapy and immunotherapy. Comprehensive molecular characterization of ICC is essential for the development of novel therapeutics. Here, we constructed two independent cohorts from two clinic centers. A comprehensive multi-omics analysis of ICC via proteomic, whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-seq) was performed. Novel ICC tumor subtypes were derived in the training cohort (n=110) using proteomic signatures and their associated activated pathways, which was further validated in a validation cohort (n=41). Three molecular subtypes, chromatin remodeling, metabolism, and chronic inflammation, with distinct prognoses in ICC were identified. The chronic inflammation subtype associated with a poor prognosis. Our random forest algorithm revealed that mutation of lysine methyltransferase 2D (KMT2D) frequently occurred in the metabolism subtype and associated with lower inflammatory activity. scRNA-seq further identified an APOE+C1QB+ macrophage subtype, which showed the capacity to reshape the chronic inflammation subtype and contribute to a poor prognosis in ICC. Altogether, with single-cell transcriptome-assisted multi-omics analysis, we identified novel molecular subtypes of ICC and validated APOE+C1QB+ tumor-associated macrophages (TAMs) as potential immunotherapy targets against ICC.
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Affiliation(s)
- Xuanwen Bao
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiong Li
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jinzhang Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Med, China
| | - Diyu Chen
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chanqi Ye
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaomeng Dai
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hang Zhou, China
| | - Yanfang Wang
- Ludwig-Maximilians-Universität München (LMU), 1, Germany
| | - Xin Li
- 5Department Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Germany
| | - Xiaoxiang Rong
- Nanfang Hospital, Southern medical University, Guangzhou 510000, Guangdong Province, People's Republic of China , GuangZhou, China
| | - Fei Cheng
- The First Affiliated Hospital, Zhejiang University School of Medicine, China
| | - Ming Jiang
- The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, China
| | - Zheng Zhu
- Brigham and Women's Hospital, boston, United States
| | - Yongfeng Ding
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, China., China
| | - Rui Sun
- Westlake University, Hang Zhou, Zhejiang Province, China
| | | | - Lingling Huang
- Westlake Omics (Hangzhou) Biotechnology, Hangzhou, Zhejiang, China
| | - Yuzhi Jin
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hang Zhou, China
| | - Bin Li
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, China
| | - Wei Wu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yixuan Guo
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hang Zhou, China
| | - Wenguang Fu
- Affiliated Hospital of Southwest Medical University, China
| | | | - Vincent Tano
- Nanyang Technological University, Singapore, Singapore
| | - Weijia Fang
- First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang, China
| | | | - Jianpeng Sheng
- First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang, China
| | - Peng Zhao
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, People's Republic of China, Hangzhou, China
| | - Jian Ruan
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hang Zhou, China
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18
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Gu Z, Du Y, Zhao X, Wang C. Diagnostic, Therapeutic, and Prognostic Value of the m 6A Writer Complex in Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:822011. [PMID: 35223847 PMCID: PMC8864226 DOI: 10.3389/fcell.2022.822011] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/25/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has poor prognosis and is usually diagnosed only at an advanced stage. Identification of novel biomarkers is critical to early diagnosis and better prognosis for HCC patients. N6-methyladenosine (m6A) RNA methylation regulators play important roles in the development of many tumors. However, the m6A writer complex, a key executor of m6A methylation modification, has not been independently investigated, and its specific bioinformatics analysis has not yet been performed in HCC. In this study, we used multiple public databases to evaluate the diagnostic, therapeutic, and prognostic value of the m6A writers in HCC. The results showed that expression levels of METTL3, VIRMA and CBLL1 were significantly increased, while expression levels of METTL14 and ZC3H13 were significantly decreased in HCC, which was closely related to clinicopathological factors, such as tumor stage and prognosis. Bioinformatics further explored the possible underlying mechanisms by which the m6A writer complex are involved in activation of tumor-promoting pathways and/or inhibition of tumor-suppressing pathways, including apoptosis, cell cycle, DNA damage response and EMT. Furthermore, we showed that the m6A writer complex is correlated with immune cell infiltration and immunoregulator expression in HCC. In conclusion, the m6A writer complex may represent a promising biomarker and target that can guide targeted therapy or immunotherapy for HCC patients.
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Affiliation(s)
- Zongting Gu
- Department of Abdominal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongxing Du
- Department of Abdominal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xueping Zhao
- School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang, China
| | - Chengfeng Wang
- Department of Abdominal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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19
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Lin SY, Chang TT, Steffen JD, Chen S, Jain S, Song W, Lin YJ, Su YH. Detection of CTNNB1 Hotspot Mutations in Cell-Free DNA from the Urine of Hepatocellular Carcinoma Patients. Diagnostics (Basel) 2021; 11:1475. [PMID: 34441409 PMCID: PMC8393790 DOI: 10.3390/diagnostics11081475] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/30/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The beta-catenin gene, CTNNB1, is among the most frequently mutated in HCC tissues. However, mutational analysis of HCC tumors is hampered by the difficulty of obtaining tissue samples using traditional biopsy. Here, we explored the feasibility of detecting tumor-derived CTNNB1 mutations in cell-free DNA (cfDNA) extracted from the urine of HCC patients. Using a short amplicon qPCR assay targeting HCC mutational hotspot CTNNB1 codons 32-37 (exon 3), we detected CTNNB1 mutations in 25% (18/73) of HCC tissues and 24% (15/62) of pre-operative HCC urine samples in two independent cohorts. Among the CTNNB1-mutation-positive patients with available matched pre- and post-operative urine (n = 13), nine showed apparent elimination (n = 7) or severalfold reduction (n = 2) of the mutation in urine following tumor resection. Four of the seven patients with no detectable mutations in postoperative urine remained recurrence-free within five years after surgery. In contrast, all six patients with mutation-positive in post-operative urine recurred, including the two with reduced mutation levels. This is the first report of association between the presence of CTNNB1 mutations in pre- and post-operative urine cfDNA and HCC recurrence with implications for minimum residual disease detection.
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Affiliation(s)
- Selena Y. Lin
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
| | - Jamin D. Steffen
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Sitong Chen
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Surbhi Jain
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Wei Song
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.D.S.); (S.C.); (S.J.); (W.S.)
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Medical College and Hospital, Tainan 701, Taiwan
| | - Ying-Hsiu Su
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA
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20
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Pezzuto F, Izzo F, De Luca P, Biffali E, Buonaguro L, Tatangelo F, Buonaguro FM, Tornesello ML. Clinical Significance of Telomerase Reverse-Transcriptase Promoter Mutations in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3771. [PMID: 34359670 PMCID: PMC8345216 DOI: 10.3390/cancers13153771] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/21/2022] Open
Abstract
Telomerase reactivation during hepatocarcinogenesis is recurrently caused by two point mutations occurring most frequently at the nucleotide -124 (95%) and occasionally at the nucleotide -146 (<5%) upstream of the TERT translational start site in hepatocellular carcinoma (HCC). In this study, we designed a droplet digital PCR (ddPCR) assay to detect TERT promoter (TERTp) nucleotide change G>A at position -124 and to quantify the mutant allele frequency (MAF) in 121 primary liver cancers, including 114 HCC along with 23 autologous cirrhotic tissues, five cholangiocarcinoma (CC), and two hepato-cholangiocarcinoma (HCC-CC). All cases were evaluated for tumour markers such as α-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). We compared the sensitivity of ddPCR and Sanger sequencing and investigated the prognostic relevance of TERTp mutations. The TERTp G>A transition was identified in 63.6% and 52.1% of HCC samples by ddPCR and Sanger sequencing, respectively. One out of 23 (4.3%) peri-tumour tissues tested positive only by ddPCR. One out of five CC (20%) and none of the HCC-CC were found concordantly mutated by the two methods. The TERTp MAF ranged from 2% to 66%, and the large majority (85.5%) of mutated samples showed a value above 20%. A statistically significant correlation was found between TERTp mutation and tumour size (p = 0.048), while an inverse correlation was observed with CA19-9 levels (p = 0.0105). Moreover, HCC patients with TERTp -124A had reduced survival. In conclusion, the single nucleotide variation G>A at position -124 in TERTp, detected either by ddPCR or by Sanger sequencing, showed a remarkable high frequency in HCC. Such mutation is associated with lower levels of CA19-9 and reduced survival in HCC patients suggesting that the TERTp status may represent a distinct signature of liver cancer subgroups.
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Affiliation(s)
- Francesca Pezzuto
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (F.P.); (F.M.B.)
| | - Francesco Izzo
- Hepatobiliary Surgery Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Napoli, Italy;
| | - Pasquale De Luca
- Research Infrastructures for Marine Biological Resources, Stazione Zoologica Anton Dohrn, 80122 Napoli, Italy; (P.D.L.); (E.B.)
| | - Elio Biffali
- Research Infrastructures for Marine Biological Resources, Stazione Zoologica Anton Dohrn, 80122 Napoli, Italy; (P.D.L.); (E.B.)
| | - Luigi Buonaguro
- Cancer Immunoregulation Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy;
| | - Fabiana Tatangelo
- Department of Pathology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Napoli, Italy;
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (F.P.); (F.M.B.)
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (F.P.); (F.M.B.)
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