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1
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Vietmeier A, Valkanas M, Lamagna N, Flett S, Gulliver D, Trun N. Bacterial nitrite production oxidizes Fe(II) bioremediating acidic abandoned coal mine drainage. Appl Environ Microbiol 2025:e0040525. [PMID: 40237488 DOI: 10.1128/aem.00405-25] [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: 02/28/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Passive remediation systems (PRSs) treating either acidic or neutral abandoned coal mine drainage (AMD) are colonized by bacteria that can bioremediate iron (Fe) through chemical cycling. Due to the low pH in acidic AMD, iron oxidation from soluble Fe(II) to precipitated Fe(III) is mainly directed by microbial oxidation. Less well described are biotic reactions that lead to iron remediation through abiotic secondary reactions. We describe here iron oxidation in acidic AMD that is mediated by the bacterial reduction of nitrate to nitrite followed by the geochemical oxidation of Fe(II). Within an acidic PRS, 4,560 bacteria cultured from the microbial community were screened for their ability to oxidize iron and to perform nitrate-dependent iron oxidation (NDFO). Iron oxidation in the culturable community was observed in every pond of the system, ranging from 2.1% to 11.4%, and NDFO was observed in every pond, ranging from 1.4% to 6.0% of the culturable bacteria. Five NDFO isolates were purified and identified as Paraburkholderia spp. One of our isolates, Paraburkholderia sp. AV18 was shown to drive NDFO through the bacterial production of nitrite that in turn chemically oxidizes Fe(II) (nitrate reduction-iron oxidation; NRIO). AV18 expressed nitrate reductase, napA, concurrent to nitrite production. Burkholderiales are found by 16S rRNA gene sequencing in every pond of the PRS. The frequency of NDFO metabolism in the culturable microbial community and abundance of Burkholderiales in the PRS suggest nitrite producers contribute to the bioremediation of iron in acidic AMD and may be an unharnessed opportunity to increase iron bioremediation in acidic conditions. IMPORTANCE Our study sheds light on a poorly defined biogeochemical interaction, nitrate-dependent iron oxidation (NDFO), that has been described in several environments. We show that bacterial nitrate reduction produces nitrite, which can chemically oxidize ferrous iron, leading to insoluble ferric iron. We show that bacteria capable of the nitrate reduction-iron oxidation (NRIO) reactions are prevalent throughout multiple passive remediation systems that treat acidic coal mine drainage, indicating this may be a widespread mechanism for iron removal under acidic conditions. In acidic coal mine remediation, iron precipitation has been shown to be solely bacterially mediated, and NRIO provides a simple mechanism for aerobic oxidation of iron in these conditions.
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Affiliation(s)
- Anna Vietmeier
- Department of Biological Sciences, Duquesne University, Pittsburgh, Pennsylvania, USA
- Department of Energy, National Energy Technology Laboratory, Pittsburgh, Pennsylvania, USA
| | - Michelle Valkanas
- Department of Biology, Earth, and Environmental Science, PennWest California, California, Pennsylvania, USA
| | - Natalie Lamagna
- Center for Environmental Research and Education, Duquesne University, Pittsburgh, Pennsylvania, USA
| | - Samuel Flett
- Department of Energy, National Energy Technology Laboratory, Pittsburgh, Pennsylvania, USA
| | - Djuna Gulliver
- Department of Energy, National Energy Technology Laboratory, Pittsburgh, Pennsylvania, USA
| | - Nancy Trun
- Department of Biological Sciences, Duquesne University, Pittsburgh, Pennsylvania, USA
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2
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Udroiu I, Marinaccio J, Goffi RS, Micheli E, Sgura A. Specificity and sensitivity of ALT-associated markers in cancer cells. FEBS Lett 2025; 599:989-1005. [PMID: 39743493 DOI: 10.1002/1873-3468.15087] [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: 09/25/2024] [Revised: 11/18/2024] [Accepted: 11/23/2024] [Indexed: 01/04/2025]
Abstract
Some tumors employ a mechanism called alternative lengthening of telomeres (ALT) to counteract telomere shortening-induced replicative senescence. Several hallmarks are used to identify cell lines and tumors as ALT-positive. Here, we analyzed a panel of ALT-positive and -negative cancer cell lines to investigate the specificity and sensibility of ALT-associated markers. We found that all the markers showed high sensitivity, indicating that cells not showing ALT markers are not ALT cells. Conversely, specificity varied significantly, i.e., many markers yield false positives. Detection of false positives may have influenced previous estimations of ALT incidence among tumors. Moreover, claims on the 'coexistence' of ALT and telomerase perhaps should be reconsidered. The findings prompt further study into the nature of these markers and their roles as either part of the ALT machinery or as by-products.
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Affiliation(s)
- Ion Udroiu
- Dipartimento di Scienze, Università degli Studi "Roma Tre", Italy
| | | | | | - Emanuela Micheli
- Dipartimento di Scienze, Università degli Studi "Roma Tre", Italy
| | - Antonella Sgura
- Dipartimento di Scienze, Università degli Studi "Roma Tre", Italy
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3
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Shah SNA, Parveen R. Differential gene expression analysis and machine learning identified structural, TFs, cytokine and glycoproteins, including SOX2, TOP2A, SPP1, COL1A1, and TIMP1 as potential drivers of lung cancer. Biomarkers 2025; 30:200-215. [PMID: 39888730 DOI: 10.1080/1354750x.2025.2461698] [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: 08/13/2024] [Accepted: 01/26/2025] [Indexed: 02/02/2025]
Abstract
BACKGROUND Lung cancer is a primary global health concern, responsible for a considerable portion of cancer-related fatalities worldwide. Understanding its molecular complexities is crucial for identifying potential targets for treatment. The goal is to slow disease progression and intervene early to prevent the development of advanced lung cancer cases. Hence, there's an urgent need for new biomarkers that can detect lung cancer in its early stages. METHODS The study conducted RNA-Seq analysis of lung cancer samples from the publicly available SRA database (NCBI SRP009408), including both control and tumour samples. The genes with differential expression between tumour and healthy tissues were identified using R and Bioconductor. Machine learning (ML) techniques, Random Forest, Lasso, XGBoost, Gradient Boosting and Elastic Net were employed to pinpoint significant genes followed by classifiers, Multilayer Perceptron (MLP), Support Vector Machines (SVM) and k-Nearest Neighbours (k-NN). Gene ontology and pathway analyses were performed on the significant differentially expressed genes (DEGs). The top genes from DEG and machine learning analyses were combined for protein-protein interaction (PPI) analysis, identifying 10 hub genes essential for lung cancer progression. RESULTS The integrated analysis of ML and DEGs revealed the significance of specific genes in lung cancer samples, identified the top 5 upregulated genes (COL11A1, TOP2A, SULF1, DIO2, MIR196A2) and the top 5 downregulated genes (PDK4, FOSB, FLYWCH1, CYB5D2, MIR328), along with their associated genes implicated in pathways or co-expression networks were identified. Among the various algorithms employed, Random Forest and XGBoost proved effective in identifying common genes, underscoring their potential significance in lung cancer pathogenesis. The MLP exhibited the highest accuracy in classifying samples using all genes. Additionally, the protein-protein interaction (PPI) analysis identified 10 hub genes that are pivotal in lung cancer pathogenesis: COL1A1, SOX2, SPP1, THBS2, POSTN, COL5A1, COL11A1, TIMP1, TOP2A and PKP1. CONCLUSION The study contributes to the early prediction of lung cancer by identifying potential biomarkers that could enhance early diagnosis and pave the way for practical clinical applications in the future. Integrating DEGs and machine learning-derived significant genes for PPI analysis offers a robust approach to uncovering critical molecular targets for lung cancer treatment.
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Affiliation(s)
| | - Rafat Parveen
- Department of Computer Science, Jamia Millia Islamia, New Delhi, India
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4
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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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5
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Nguyen AL, Facey COB, Boman BM. The Significance of Aldehyde Dehydrogenase 1 in Cancers. Int J Mol Sci 2024; 26:251. [PMID: 39796106 PMCID: PMC11720537 DOI: 10.3390/ijms26010251] [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: 11/14/2024] [Revised: 12/16/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
The goal of this paper is to discuss the role of ALDH isozymes in different cancers, review advances in ALDH1-targeting cancer therapies, and explore a mechanism that explains how ALDH expression becomes elevated during cancer development. ALDH is often overexpressed in cancer, and each isoform has a unique expression pattern and a distinct role in different cancers. The abnormal expression of ALDHs in different cancer types (breast, colorectal, lung, gastric, cervical, melanoma, prostate, and renal) is presented and correlated with patient prognosis. ALDH plays a significant role in various cellular functions, such as metabolism, oxidative stress response, detoxification, and cellular differentiation. Among the ALDH families, ALDH1 has gained considerable attention as a cancer stem cell (CSC) marker due to its significant role in the maintenance of stemness and the differentiation of stem cells (SCs), along with its involvement in tumorigenesis. A description of the cellular mechanisms and physiology of ALDH1 that underlies cancer development is provided. Moreover, current advances in ALDH1-targeting cancer therapies are discussed.
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Affiliation(s)
- Anh L. Nguyen
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA;
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA;
| | - Caroline O. B. Facey
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA;
| | - Bruce M. Boman
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA;
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA;
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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6
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Ma W, Tang W, Kwok JS, Tong AH, Lo CW, Chu AT, Chung BH. A review on trends in development and translation of omics signatures in cancer. Comput Struct Biotechnol J 2024; 23:954-971. [PMID: 38385061 PMCID: PMC10879706 DOI: 10.1016/j.csbj.2024.01.024] [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: 10/27/2023] [Revised: 01/31/2024] [Accepted: 01/31/2024] [Indexed: 02/23/2024] Open
Abstract
The field of cancer genomics and transcriptomics has evolved from targeted profiling to swift sequencing of individual tumor genome and transcriptome. The steady growth in genome, epigenome, and transcriptome datasets on a genome-wide scale has significantly increased our capability in capturing signatures that represent both the intrinsic and extrinsic biological features of tumors. These biological differences can help in precise molecular subtyping of cancer, predicting tumor progression, metastatic potential, and resistance to therapeutic agents. In this review, we summarized the current development of genomic, methylomic, transcriptomic, proteomic and metabolic signatures in the field of cancer research and highlighted their potentials in clinical applications to improve diagnosis, prognosis, and treatment decision in cancer patients.
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Affiliation(s)
- Wei Ma
- Hong Kong Genome Institute, Hong Kong, China
| | - Wenshu Tang
- Hong Kong Genome Institute, Hong Kong, China
| | | | | | | | | | - Brian H.Y. Chung
- Hong Kong Genome Institute, Hong Kong, China
- Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hong Kong Genome Project
- Hong Kong Genome Institute, Hong Kong, China
- Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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7
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Valentine A, Bosart K, Bush W, Bouley RA, Petreaca RC. Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers. Cancer Genet 2024; 288-289:82-91. [PMID: 39488870 DOI: 10.1016/j.cancergen.2024.10.007] [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: 07/12/2024] [Revised: 09/22/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024]
Abstract
ADAR1 (Adenosine deaminase action on RNA1) is involved in post-transcriptional RNA editing. ADAR1 mutations have been identified in many cancers but its role in tumor formation is still not well understood. Here we used available cancer genomes deposited on CSOMIC and cBioPortal to identify and characterize mutations and changes in ADAR1 expression in cancer cells. We identify several high frequency substitutions including one at R767 which is located in one of the dsRNA interacting domains. In silico protein structure analysis suggest the R767 mutations affect the protein stability and are likely to destabilize interaction with dsRNA. Gene expression analysis shows that in samples with under-expressed ADAR1, there is a statistically significant increase in expression of BLCAP (Bladder Cancer Associated Protein). Although BLCAP was initially identified in bladder cancers, more recent evidence shows that it is a tumor suppressor and BLCAP mutations have been detected in many cancer cells. Epistatic analysis using the cBioPortal mutual exclusivity calculator for the TCGA pan-cancer data shows that co-mutations between ADAR1 and other genes regulated by it are likely in cancer cells except for PTEN, AKT1 and BLCAP. This suggests that when ADAR1 function is impaired, PTEN, AKT1 and BLCAP become essential for survival of cancer cells. We also identified several samples with high mutation burden between ADAR1 and other genes regulated primarily in endometrial cancers. Finally, we show that the deaminase domain is highly conserved in metazoans and mutations within conserved residues do occur in human cancers suggesting that destabilization of the enzyme function is contributing to cancer development.
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Affiliation(s)
- Anna Valentine
- Biology Program, The Ohio State University, Marion, United States
| | - Korey Bosart
- Cancer Biology, The James Comprehensive Cancer Center, OSU, United States
| | - Wesley Bush
- Biology Program, The Ohio State University, Marion, United States; Cancer Biology, The James Comprehensive Cancer Center, OSU, United States
| | - Renee A Bouley
- Department of Chemistry and Biochemistry, The Ohio State University, United States
| | - Ruben C Petreaca
- Cancer Biology, The James Comprehensive Cancer Center, OSU, United States; Department of Molecular Genetics, The Ohio State University, United States.
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8
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Mizuno Y, Kawakami T, Higano D, Miyairi S, Asakura A, Kawakami F, Sato K, Matsuzawa S, Nishina S, Sakai H, Higuchi Y, Matsuda K, Nakazawa H, Ishida F. CCL22 mutations in large granular lymphocytic leukemia. Haematologica 2024; 109:3067-3070. [PMID: 38813714 PMCID: PMC11367240 DOI: 10.3324/haematol.2024.285404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/17/2024] [Indexed: 05/31/2024] Open
Abstract
Not available.
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Affiliation(s)
- Yuga Mizuno
- Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto
| | - Toru Kawakami
- Department of Hematology, Shinshu University School of Medicine, Matsumoto
| | - Daigo Higano
- Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto
| | - Shotaro Miyairi
- Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto
| | - Ami Asakura
- Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto
| | - Fumihiro Kawakami
- Department of Hematology, Shinshu University School of Medicine, Matsumoto
| | - Keijiro Sato
- Department of Hematology, Nagano Red Cross Hospital, Nagano
| | - Shuji Matsuzawa
- Department of Hematology, Shinshu University School of Medicine, Matsumoto
| | - Sayaka Nishina
- Department of Hematology, Shinshu University School of Medicine, Matsumoto
| | - Hitoshi Sakai
- Department of Hematology, Shinshu University School of Medicine, Matsumoto
| | - Yumiko Higuchi
- Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; Department of Biomedical Laboratory Sciences, Shinshu University School of Medicine, Matsumoto
| | - Kazuyuki Matsuda
- Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; Department of Health and Medical Sciences, Graduate School of Medicine, Shinshu University, Matsumoto
| | - Hideyuki Nakazawa
- Department of Hematology, Shinshu University School of Medicine, Matsumoto
| | - Fumihiro Ishida
- Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; Department of Hematology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Biomedical Laboratory Sciences, Shinshu University School of Medicine, Matsumoto.
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9
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Boldinova EO, Baranovskiy AG, Filina YV, Miftakhova RR, Shamsutdinova YF, Tahirov TH, Makarova AV. PrimPol Variant V102A with Altered Primase and Polymerase Activities. J Mol Biol 2024; 436:168542. [PMID: 38492718 DOI: 10.1016/j.jmb.2024.168542] [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: 01/05/2024] [Revised: 03/10/2024] [Accepted: 03/12/2024] [Indexed: 03/18/2024]
Abstract
PrimPol is a human DNA primase-polymerase which restarts DNA synthesis beyond DNA lesions and non-B DNA structures blocking replication. Disfunction of PrimPol in cells leads to slowing of DNA replication rates in mitochondria and nucleus, accumulation of chromosome aberrations, cell cycle delay, and elevated sensitivity to DNA-damaging agents. A defective PrimPol has been suggested to be associated with the development of ophthalmic diseases, elevated mitochondrial toxicity of antiviral drugs and increased cell resistance to chemotherapy. Here, we describe a rare missense PrimPol variant V102A with altered biochemical properties identified in patients suffering from ovarian and cervical cancer. The Val102 to Ala substitution dramatically reduced both the primase and DNA polymerase activities of PrimPol as well as specifically decreased its ability to incorporate ribonucleotides. Structural analysis indicates that the V102A substitution can destabilize the hydrophobic pocket adjacent to the active site, affecting dNTP binding and catalysis.
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Affiliation(s)
- Elizaveta O Boldinova
- National Research Center "Kurchatov Institute", Kurchatov sq. 2, 123182 Moscow, Russia; Institute of Gene Biology, Russian Academy of Sciences, Vavilova 34 / 5, 119334 Moscow, Russia
| | - Andrey G Baranovskiy
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Yulia V Filina
- "Translational Oncology" Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya 18, 420008 Kazan, Russia
| | - Regina R Miftakhova
- "Translational Oncology" Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya 18, 420008 Kazan, Russia
| | - Yana F Shamsutdinova
- Chemotherapy Department №1, Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan Named After Prof. M.Z. Sigal, Sibirskiy trakt 29, 420029 Kazan, Russia
| | - Tahir H Tahirov
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Alena V Makarova
- National Research Center "Kurchatov Institute", Kurchatov sq. 2, 123182 Moscow, Russia; Institute of Gene Biology, Russian Academy of Sciences, Vavilova 34 / 5, 119334 Moscow, Russia.
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10
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Gromova AS, Boldinova EO, Kim DV, Chuprov-Netochin RN, Leonov SV, Pustovalova MV, Zharkov DO, Makarova AV. Response of PRIMPOL-Knockout Human Lung Adenocarcinoma A549 Cells to Genotoxic Stress. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:1933-1943. [PMID: 38105210 DOI: 10.1134/s0006297923110214] [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: 12/09/2022] [Revised: 08/08/2023] [Accepted: 09/15/2023] [Indexed: 12/19/2023]
Abstract
Human DNA primase/polymerase PrimPol synthesizes DNA primers de novo after replication fork stalling at the sites of DNA damage, thus contributing to the DNA damage tolerance. The role of PrimPol in response to the different types of DNA damage is poorly understood. We knocked out the PRIMPOL gene in the lung carcinoma A549 cell line and characterized the response of the obtained cells to the DNA damage caused by hydrogen peroxide, methyl methanesulfonate (MMS), cisplatin, bleomycin, and ionizing radiation. The PRIMPOL knockout reduced the number of proliferating cells and cells in the G2 phase after treatment with MMS and caused a more pronounced delay of the S phase in the cisplatin-treated cells. Ionizing radiation at a dose of 10 Gy significantly increased the content of apoptotic cells among the PRIMPOL-deficient cells, while the proportion of cells undergoing necroptosis increased in both parental and knockout cells at any radiation dose. The viability of PRIMPOL-deficient cells upon the hydrogen peroxide-induced oxidative stress increased compared to the control cells, as determined by the methyl tetrazolium (MTT) assay. The obtained data indicate the involvement of PRIMPOL in the modulation of adaptive cell response to various types of genotoxic stress.
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Affiliation(s)
- Anastasia S Gromova
- Institute of Molecular Genetics, Kurchatov Institute National Research Center, Moscow, 123182, Russia
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia
| | - Elizaveta O Boldinova
- Institute of Molecular Genetics, Kurchatov Institute National Research Center, Moscow, 123182, Russia
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia
| | - Daria V Kim
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
- Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Roman N Chuprov-Netochin
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, 141700, Russia
| | - Sergey V Leonov
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, 141700, Russia
- Institute of Cell Biophysics of the Russian Academy of Sciences, Pushchino, 142290, Russia
| | - Margarita V Pustovalova
- School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, 141700, Russia
| | - Dmitry O Zharkov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
- Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Alena V Makarova
- Institute of Molecular Genetics, Kurchatov Institute National Research Center, Moscow, 123182, Russia.
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia
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11
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Xie M, Zhang L, Han L, Huang L, Huang Y, Yang M, Zhang N. The ASH1L-AS1-ASH1L axis controls NME1-mediated activation of the RAS signaling in gastric cancer. Oncogene 2023; 42:3435-3445. [PMID: 37805663 DOI: 10.1038/s41388-023-02855-8] [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: 04/03/2023] [Revised: 09/21/2023] [Accepted: 09/28/2023] [Indexed: 10/09/2023]
Abstract
Gastric cancer (GC) is one of the most leading cause of malignancies. However, the molecular mechanisms underlying stomach carcinogenesis remain incompletely understood. Dysregulated genetic and epigenetic alternations significantly contribute to GC development. Here, we report that ASH1L and its antisense lncRNA ASH1L-AS1, which are transcribed from the most significant GC-risk signal at 1q22, act as novel oncogenes. The high levels of ASH1L or lncRNA ASH1L-AS1 expression in GC specimens are associated with worse prognosis of patients. In line with this, ASH1L and ASH1L-AS1 are functionally important in promoting GC disease progression. LncRNA ASH1L-AS1 up-regulates ASH1L transcription, increases histone methyltransferase ASH1L expression and elevates genome-wide H3K4me3 modification levels in GC cells. Furthermore, ASH1L-AS1 directly interacts with transcription factor NME1 protein to form the ASH1L-AS1-NME1 ribonucleoprotein, which transcriptionally promotes expression of ASH1L, ASH1L-AS1, KRAS and RAF1, and activates the RAS signaling pathway in GC cells. Taken together, our data demonstrated that the ASH1L-AS1-ASH1L regulatory axis controls histone modification reprogram and activation of the RAS signaling in cancers. Thus, ASH1L-AS1 might be a novel targets of GC therapeutics and diagnosis in the clinic.
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Affiliation(s)
- Mengyu Xie
- Departemnt of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Long Zhang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Linying Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Nasha Zhang
- Departemnt of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
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12
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Lin YT, Li CF, Wu HC, Jan YH, Kuo YH. Case report: Heterogenous SMARCA4-deficient thoracic non-small cell lung carcinoma with various responses to nivolumab. Front Immunol 2023; 14:1131448. [PMID: 37051241 PMCID: PMC10083322 DOI: 10.3389/fimmu.2023.1131448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 03/10/2023] [Indexed: 03/29/2023] Open
Abstract
SMARCA4-deficient non-small cell carcinoma is an aggressive neoplasm with poor outcome. Several studies have highlighted its immunochemistry, pathophysiology, and underlying mechanisms, but studies of its definite treatment are few. Here, we report on a 69-year-old male with heterogenous pathological presentations of SMARCA4-deficient non-small cell carcinoma. He initially presented with neck lymphadenopathies. Immunohistochemistry staining and genomic profiling confirmed the diagnosis of SMARCA4-deficient non-small cell carcinoma. The patient responded well to immune checkpoint inhibitors with nivolumab. However, new lesions with various pathological presentations and various responses to nivolumab appeared during the treatment course. The patient survived more than 3 years from the initial diagnosis. This case shows the efficacy of nivolumab to treat SMARCA4-deficient non-small cell lung carcinoma.
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Affiliation(s)
- Yun-Tzu Lin
- Department of Oncology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chien-Feng Li
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
- Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Hung-Chang Wu
- Department of Oncology, Chi-Mei Medical Center, Tainan, Taiwan
- College of Pharmacy and Science, Chia Nan University, Tainan, Taiwan
| | | | - Yu-Hsuan Kuo
- Department of Oncology, Chi-Mei Medical Center, Tainan, Taiwan
- College of Pharmacy and Science, Chia Nan University, Tainan, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
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13
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Islam SA, Díaz-Gay M, Wu Y, Barnes M, Vangara R, Bergstrom EN, He Y, Vella M, Wang J, Teague JW, Clapham P, Moody S, Senkin S, Li YR, Riva L, Zhang T, Gruber AJ, Steele CD, Otlu B, Khandekar A, Abbasi A, Humphreys L, Syulyukina N, Brady SW, Alexandrov BS, Pillay N, Zhang J, Adams DJ, Martincorena I, Wedge DC, Landi MT, Brennan P, Stratton MR, Rozen SG, Alexandrov LB. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. CELL GENOMICS 2022; 2:None. [PMID: 36388765 PMCID: PMC9646490 DOI: 10.1016/j.xgen.2022.100179] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 04/10/2022] [Accepted: 08/31/2022] [Indexed: 12/09/2022]
Abstract
Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.
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Affiliation(s)
- S.M. Ashiqul Islam
- 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
| | - Marcos Díaz-Gay
- 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
| | - Yang Wu
- Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke NUS Medical School, Singapore 169857, Singapore
| | - Mark Barnes
- 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
| | - Raviteja Vangara
- 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
| | - Erik N. Bergstrom
- 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
| | - Yudou He
- 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
| | - Mike Vella
- NVIDIA Corporation, 2788 San Tomas Expressway, Santa Clara, CA 95051, USA
| | - Jingwei Wang
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - Jon W. Teague
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - Peter Clapham
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - Sarah Moody
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - Sergey Senkin
- Genetic Epidemiology Group, International Agency for Research on Cancer, Cedex 08, 69372 Lyon, France
| | - Yun Rose Li
- Departments of Radiation Oncology and Cancer Genetics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Laura Riva
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - Tongwu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
| | - Andreas J. Gruber
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF, UK
- Manchester Cancer Research Centre, The University of Manchester, Manchester M20 4GJ, UK
- Department of Biology, University of Konstanz, Universitaetsstrasse 10, D-78464 Konstanz, Germany
| | - Christopher D. Steele
- Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK
| | - 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
| | - Azhar Khandekar
- 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
| | - Ammal Abbasi
- 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
| | - Laura Humphreys
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | | | - Samuel W. Brady
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Boian S. Alexandrov
- Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
| | - Nischalan Pillay
- Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK
- Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK
| | - Jinghui Zhang
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - David J. Adams
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - Iñigo Martincorena
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - David C. Wedge
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF, UK
- Manchester Cancer Research Centre, The University of Manchester, Manchester M20 4GJ, UK
| | - Maria Teresa Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
| | - Paul Brennan
- Genetic Epidemiology Group, International Agency for Research on Cancer, Cedex 08, 69372 Lyon, France
| | - Michael R. Stratton
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
| | - Steven G. Rozen
- Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke NUS Medical School, Singapore 169857, Singapore
| | - 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
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14
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Fan B, Huang Y, Zhang H, Chen T, Tao S, Wang X, Wen S, Wang H, Lin Z, Liu T, Zhang H, He T, Li X. Analysis of genetic profiling, pathomics signature, and prognostic features of primary lymphoepithelioma‐like carcinoma of the renal pelvis. Mol Oncol 2022; 16:3666-3688. [PMID: 36052737 PMCID: PMC9580896 DOI: 10.1002/1878-0261.13307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 07/27/2022] [Accepted: 08/22/2022] [Indexed: 11/24/2022] Open
Abstract
The genetic features of primary lymphoepithelioma‐like carcinoma (LELC) of the upper urinary tract have not been systematically explored. In this study, tumor mutation profiling was performed using whole‐genome sequencing in two patients with LELC of the renal pelvis. Novel candidate variants relevant to known disease genes were selected using rare‐variant burden analysis. Subsequently, a population‐based study was performed using the Surveillance, Epidemiology, and End Results (SEER), PubMed, MEDLINE, Embase, and Scopus databases to explore clinical features and prognostic risk factors. Immunohistochemical analysis revealed seven positive cytokeratin‐associated markers in tumor cells and five positive lymphocyte‐associated markers in and around the tumor area. Sub‐sequently, we identified KDM6A as the susceptibility gene and LEPR as the driver gene by Sanger sequencing in case 2 of LELC of the renal pelvis. Three mutation sites of the existing targeted drugs were screened: CA9, a therapeutic target for zonisamide; ARVCF, a therapeutic target for bupropion; and PLOD3, a therapeutic target for vitamin C. In a population‐based study, patients with primary LELC of the upper urinary tract had clinical outcomes similar to those of patients with primary upper urinary tract urothelial carcinoma (UUT‐UC) before and after propensity score matching at 1 : 5. Focal subtype was an independent prognostic factor for the overall survival of patients with LELC of the upper urinary tract. The carcinogenesis of primary LELC may be due to different genetic variations, including single‐nucleotide variants, insertion and deletions, structural variations, and repeat regions, which may provide the basis for clinical diagnosis and treatment. The prognosis of LELC in the upper urinary tract is similar to that of UUT‐UC. We suggest that the focal subtype can serve as a prognostic factor for LELC of the upper urinary tract; however, further studies are required to confirm this.
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Affiliation(s)
- Bo Fan
- Department of Urology Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
| | - Yuanbin Huang
- Department of Urology Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
| | - Hongshuo Zhang
- Department of Biochemistry, Institute of Glycobiology Dalian Medical University 116000 Dalian Liaoning Province China
| | - Tingyu Chen
- Department of Clinical Medicine Dalian Medical University 116000 Dalian Liaoning Province China
| | - Shenghua Tao
- Department of Urology Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
| | - Xiaogang Wang
- Department of Urology Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
| | - Shuang Wen
- Department of Pathology, Dalian Friendship Hospital 116000 Dalian Liaoning Province China
| | - Honglong Wang
- Department of Pathology, Dalian Friendship Hospital 116000 Dalian Liaoning Province China
| | - Zhe Lin
- Ethics Committee Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
| | - Tianqing Liu
- Department of Pathology, Dalian Friendship Hospital 116000 Dalian Liaoning Province China
| | - Hongxian Zhang
- Department of Urology Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
| | - Tao He
- Department of Urology Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
| | - Xiancheng Li
- Department of Urology Second Affiliated Hospital of Dalian Medical University 116000 Dalian Liaoning Province China
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15
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Pogribna M, Word B, Lyn-Cook B, Hammons G. Effect of titanium dioxide nanoparticles on histone modifications and histone modifying enzymes expression in human cell lines. Nanotoxicology 2022; 16:409-424. [DOI: 10.1080/17435390.2022.2085206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Affiliation(s)
- Marta Pogribna
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
| | - Beverly Word
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
| | - Beverly Lyn-Cook
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
| | - George Hammons
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
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16
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Felip E, Gutiérrez-Chamorro L, Gómez M, Garcia-Vidal E, Romeo M, Morán T, Layos L, Pérez-Roca L, Riveira-Muñoz E, Clotet B, Fernandez PL, Mesía R, Martínez-Cardús A, Ballana E, Margelí M. Modulation of DNA Damage Response by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase (SAMHD1) Determines Prognosis and Treatment Efficacy in Different Solid Tumor Types. Cancers (Basel) 2022; 14:641. [PMID: 35158911 PMCID: PMC8833711 DOI: 10.3390/cancers14030641] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/19/2022] [Accepted: 01/21/2022] [Indexed: 12/31/2022] Open
Abstract
SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase with important roles in the control of cell proliferation and apoptosis, either through the regulation of intracellular dNTPs levels or the modulation of the DNA damage response. However, SAMHD1's role in cancer evolution is still unknown. We performed the first in-depth study of SAMHD1's role in advanced solid tumors, by analyzing samples of 128 patients treated with chemotherapy agents based on platinum derivatives and/or antimetabolites, developing novel in vitro knock-out models to explore the mechanisms driving SAMHD1 function in cancer. Low (or no) expression of SAMHD1 was associated with a positive prognosis in breast, ovarian, and non-small cell lung cancer (NSCLC) cancer patients. A predictive value was associated with low-SAMHD1 expression in NSCLC and ovarian patients treated with antimetabolites in combination with platinum derivatives. In vitro, SAMHD1 knock-out cells showed increased γ-H2AX and apoptosis, suggesting that SAMHD1 depletion induces DNA damage leading to cell death. In vitro treatment with platinum-derived drugs significantly enhanced γ-H2AX and apoptotic markers expression in knock-out cells, indicating a synergic effect of SAMHD1 depletion and platinum-based treatment. SAMHD1 expression represents a new strong prognostic and predictive biomarker in solid tumors and, thus, modulation of the SAMHD1 function may constitute a promising target for the improvement of cancer therapy.
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Affiliation(s)
- Eudald Felip
- AIDS Research Institute-IrsiCaixa, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (E.F.); (L.G.-C.); (E.G.-V.); (E.R.-M.); (B.C.)
- Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol (HGTiP), 08916 Badalona, Spain; (M.R.); (T.M.); (L.L.); (R.M.); (A.M.-C.)
- (B-ARGO) Badalona Applied Research Group in Oncology, (IGTP), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Lucía Gutiérrez-Chamorro
- AIDS Research Institute-IrsiCaixa, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (E.F.); (L.G.-C.); (E.G.-V.); (E.R.-M.); (B.C.)
| | - Maica Gómez
- Department of Pathology, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (M.G.); (P.L.F.)
| | - Edurne Garcia-Vidal
- AIDS Research Institute-IrsiCaixa, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (E.F.); (L.G.-C.); (E.G.-V.); (E.R.-M.); (B.C.)
| | - Margarita Romeo
- Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol (HGTiP), 08916 Badalona, Spain; (M.R.); (T.M.); (L.L.); (R.M.); (A.M.-C.)
- (B-ARGO) Badalona Applied Research Group in Oncology, (IGTP), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Teresa Morán
- Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol (HGTiP), 08916 Badalona, Spain; (M.R.); (T.M.); (L.L.); (R.M.); (A.M.-C.)
- (B-ARGO) Badalona Applied Research Group in Oncology, (IGTP), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Laura Layos
- Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol (HGTiP), 08916 Badalona, Spain; (M.R.); (T.M.); (L.L.); (R.M.); (A.M.-C.)
- (B-ARGO) Badalona Applied Research Group in Oncology, (IGTP), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Laia Pérez-Roca
- Banc de Tumors, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain;
| | - Eva Riveira-Muñoz
- AIDS Research Institute-IrsiCaixa, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (E.F.); (L.G.-C.); (E.G.-V.); (E.R.-M.); (B.C.)
| | - Bonaventura Clotet
- AIDS Research Institute-IrsiCaixa, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (E.F.); (L.G.-C.); (E.G.-V.); (E.R.-M.); (B.C.)
| | - Pedro Luis Fernandez
- Department of Pathology, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (M.G.); (P.L.F.)
| | - Ricard Mesía
- Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol (HGTiP), 08916 Badalona, Spain; (M.R.); (T.M.); (L.L.); (R.M.); (A.M.-C.)
- (B-ARGO) Badalona Applied Research Group in Oncology, (IGTP), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Anna Martínez-Cardús
- Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol (HGTiP), 08916 Badalona, Spain; (M.R.); (T.M.); (L.L.); (R.M.); (A.M.-C.)
- (B-ARGO) Badalona Applied Research Group in Oncology, (IGTP), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Ester Ballana
- AIDS Research Institute-IrsiCaixa, IGTP (Health Research Institute Germans Trias i Pujol), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (E.F.); (L.G.-C.); (E.G.-V.); (E.R.-M.); (B.C.)
| | - Mireia Margelí
- Medical Oncology Department, Catalan Institute of Oncology-Badalona, Hospital Germans Trias i Pujol (HGTiP), 08916 Badalona, Spain; (M.R.); (T.M.); (L.L.); (R.M.); (A.M.-C.)
- (B-ARGO) Badalona Applied Research Group in Oncology, (IGTP), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
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17
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Sun Y, Wang Y, Liu S, Han B, Sun M, Wang J. Significance of Vasohibin 1 in Cancer Patients: A Systematic Review and Meta analysis. J Cancer Res Ther 2022; 18:567-575. [DOI: 10.4103/jcrt.jcrt_281_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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18
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Targeting Cancer by Using Nanoparticles to Modulate RHO GTPase Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1357:115-127. [DOI: 10.1007/978-3-030-88071-2_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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19
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Lee SH, Golinska M, Griffiths JR. HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells. Cells 2021; 10:2371. [PMID: 34572020 PMCID: PMC8472468 DOI: 10.3390/cells10092371] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/22/2022] Open
Abstract
In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.
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Affiliation(s)
- Shen-Han Lee
- Department of Otorhinolaryngology, Hospital Sultanah Bahiyah, KM6 Jalan Langgar, Alor Setar 05460, Kedah, Malaysia
| | - Monika Golinska
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; (M.G.); (J.R.G.)
- Department of Physics, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK
| | - John R. Griffiths
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; (M.G.); (J.R.G.)
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20
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Bainbridge LJ, Teague R, Doherty AJ. Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication. Nucleic Acids Res 2021; 49:4831-4847. [PMID: 33744934 PMCID: PMC8136793 DOI: 10.1093/nar/gkab176] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/01/2021] [Accepted: 03/05/2021] [Indexed: 12/25/2022] Open
Abstract
To bypass a diverse range of fork stalling impediments encountered during genome replication, cells possess a variety of DNA damage tolerance (DDT) mechanisms including translesion synthesis, template switching, and fork reversal. These pathways function to bypass obstacles and allow efficient DNA synthesis to be maintained. In addition, lagging strand obstacles can also be circumvented by downstream priming during Okazaki fragment generation, leaving gaps to be filled post-replication. Whether repriming occurs on the leading strand has been intensely debated over the past half-century. Early studies indicated that both DNA strands were synthesised discontinuously. Although later studies suggested that leading strand synthesis was continuous, leading to the preferred semi-discontinuous replication model. However, more recently it has been established that replicative primases can perform leading strand repriming in prokaryotes. An analogous fork restart mechanism has also been identified in most eukaryotes, which possess a specialist primase called PrimPol that conducts repriming downstream of stalling lesions and structures. PrimPol also plays a more general role in maintaining efficient fork progression. Here, we review and discuss the historical evidence and recent discoveries that substantiate repriming as an intrinsic replication restart pathway for maintaining efficient genome duplication across all domains of life.
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Affiliation(s)
- Lewis J Bainbridge
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, BN1 9RQ, UK
| | - Rebecca Teague
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, BN1 9RQ, UK
| | - Aidan J Doherty
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, BN1 9RQ, UK
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21
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Cheng C, Liu L, Bao Y, Yi J, Quan W, Xue Y, Sun L, Zhang Y. SUVA: splicing site usage variation analysis from RNA-seq data reveals highly conserved complex splicing biomarkers in liver cancer. RNA Biol 2021; 18:157-171. [PMID: 34152934 DOI: 10.1080/15476286.2021.1940037] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Most of the current alternative splicing (AS) analysis tools are powerless to analyse complex splicing. To address this, we developed SUVA (Splice sites Usage Variation Analysis) that decomposes complex splicing events into five types of splice junction pairs. By analysing real and simulated data, SUVA showed higher sensitivity and accuracy in detecting AS events than the compared methods. Notably, SUVA detected extensive complex AS events and screened out 69 highly conserved and dominant AS events associated with cancer. The cancer-associated complex AS events in FN1 and the co-regulated RNA-binding proteins were significantly correlated with patient survival.
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Affiliation(s)
- Chao Cheng
- ABLife BioBigData Institute, Wuhan, Hubei China.,Center for Genome Analysis, ABLife Inc., Wuhan, Hubei China
| | - Lei Liu
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun China
| | - Yongli Bao
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun China
| | - Jingwen Yi
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun China
| | - Weili Quan
- ABLife BioBigData Institute, Wuhan, Hubei China
| | - Yaqiang Xue
- ABLife BioBigData Institute, Wuhan, Hubei China
| | - Luguo Sun
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun China
| | - Yi Zhang
- ABLife BioBigData Institute, Wuhan, Hubei China.,Center for Genome Analysis, ABLife Inc., Wuhan, Hubei China
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22
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Niu L, Dang C, Li L, Guo N, Xu Y, Li X, Xu Q, Cheng L, Zhang L, Liu L. Next-generation sequencing-based identification of EGFR and NOTCH2 complementary mutations in non-small cell lung cancer. Oncol Lett 2021; 22:594. [PMID: 34149905 PMCID: PMC8200943 DOI: 10.3892/ol.2021.12855] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022] Open
Abstract
Although targeted therapy has emerged as an effective treatment strategy for non-small cell lung cancer (NSCLC), some patients cannot benefit from such therapy due to the limited number of therapeutic targets. The present study aimed to identify mutated genes associated with clinicopathological characteristics and prognosis and to screen for mutations that are not concurrent with applicable drug target sites in patients with NSCLC. Tumor tissue and blood samples were obtained from 97 patients with NSCLC. A lung cancer-specific panel of 55 genes was established and analyzed using next-generation sequencing (NGS). The results obtained from the clinical cohort were compared with the NSCLC dataset from The Cancer Genome Atlas (TCGA). Subsequently, 25 driver genes were identified by taking the intersection of the 55 lung-cancer-specific genes with three databases, namely, the Catalog of Somatic Mutations in Cancer database, the Network of Cancer Genes database and Vogelstein's list. Functional annotation and protein-protein interaction analysis were conducted on these 25 driver genes. The χ2 test and logistic regression were used to evaluate the association between mutations in the 25 driver genes and the clinicopathological characteristics of 97 patients, and phosphatase and tensin homolog (PTEN) and kirsten rat sarcoma viral oncogene homolog (KRAS) were associated with stage at diagnosis and sex, respectively, while epidermal growth factor receptor (EGFR) was associated with sex, stage at diagnosis, metastasis, CEA and CYFRA21-1. Moreover, the association between the 25 driver gene mutations and overall survival were examined using Cox regression analysis. Age and Notch homolog 2 (NOTCH2) mutations were independent prognostic factors in TCGA dataset. The correlations between statistically significant mutations in EGFR, KRAS, PTEN and NOTCH2 were further examined, both in the clinical data and TCGA dataset. There was a negative correlation between EGFR and NOTCH2 mutations (correlation coefficient, −0.078; P=0.027). Thus, the present study highlights the importance of NOTCH2 mutations and might provide novel therapeutic options for patients with NSCLC who do not harbor EGFR mutations.
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Affiliation(s)
- Lin Niu
- Department of Human Anatomy, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Chunyan Dang
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Lin Li
- Department of Human Anatomy, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Na Guo
- Department of Immunology, Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Ying Xu
- Department of Immunology, Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Xiangling Li
- Department of Pathology, Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Qian Xu
- Basic Medical Institute, Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Luyang Cheng
- Department of Immunology, Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Li Zhang
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
| | - Lei Liu
- Department of Immunology, Chengde Medical University, Chengde, Hebei 067000, P.R. China
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23
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Chen X, Lin X, Pang G, Deng J, Xie Q, Zhang Z. Significance of KDM6A mutation in bladder cancer immune escape. BMC Cancer 2021; 21:635. [PMID: 34051747 PMCID: PMC8164329 DOI: 10.1186/s12885-021-08372-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/06/2021] [Indexed: 12/14/2022] Open
Abstract
Background Bladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; however, its effects on tumour progression and clinical outcome in BC remain unclear. Here, we explored the potential role of KDM6A in regulating the antitumor immune response. Methods We mined The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for somatic mutation and clinical data in patients with BC. Results We found frequent mutations in 12 genes in both cohorts, including TP53, KDM6A, CSMD3, MUC16, STAG2, PIK3CA, ARID1A, RB1, EP300, ERBB2, ERBB3, and FGFR3. The frequency o KDM6A mutations in the TCGA and ICGC datasets was 25.97 and 24.27%, respectively. In addition, KDM6A mutation was associated with a lower number of tumour-infiltrating immune cells (TIICs) and indicated a state of immune tolerance. KDM6A mutation was associated with lower KDM6A mRNA level compared with that in samples carrying the wild-type gene. Further, survival analysis showed that the prognosis of patients with low KDM6A expression was worse than that with high KDM6A expression. Using the CIBERSORT algorithm, Tumor Immune Estimation Resource site, and Gene Set Enrichment Analysis, we found that KDM6A mutation downregulated nine signalling pathways that participate in the immune system and attenuated the tumour immune response. Conclusion Overall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08372-9.
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Affiliation(s)
- Xingxing Chen
- Department of Urology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Kangning Road No.79, in Zhuhai city, Guang Dong Province, Zhuhai, People's Republic of China
| | - Xuehua Lin
- Department of Urology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Kangning Road No.79, in Zhuhai city, Guang Dong Province, Zhuhai, People's Republic of China
| | - Guofu Pang
- Department of Urology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Kangning Road No.79, in Zhuhai city, Guang Dong Province, Zhuhai, People's Republic of China
| | - Jian Deng
- Department of Urology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Kangning Road No.79, in Zhuhai city, Guang Dong Province, Zhuhai, People's Republic of China
| | - Qun Xie
- Department of Urology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Kangning Road No.79, in Zhuhai city, Guang Dong Province, Zhuhai, People's Republic of China
| | - Zhengrong Zhang
- Department of Urology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Kangning Road No.79, in Zhuhai city, Guang Dong Province, Zhuhai, People's Republic of China.
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24
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Biology of the mRNA Splicing Machinery and Its Dysregulation in Cancer Providing Therapeutic Opportunities. Int J Mol Sci 2021; 22:ijms22105110. [PMID: 34065983 PMCID: PMC8150589 DOI: 10.3390/ijms22105110] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/13/2022] Open
Abstract
Dysregulation of messenger RNA (mRNA) processing—in particular mRNA splicing—is a hallmark of cancer. Compared to normal cells, cancer cells frequently present aberrant mRNA splicing, which promotes cancer progression and treatment resistance. This hallmark provides opportunities for developing new targeted cancer treatments. Splicing of precursor mRNA into mature mRNA is executed by a dynamic complex of proteins and small RNAs called the spliceosome. Spliceosomes are part of the supraspliceosome, a macromolecular structure where all co-transcriptional mRNA processing activities in the cell nucleus are coordinated. Here we review the biology of the mRNA splicing machinery in the context of other mRNA processing activities in the supraspliceosome and present current knowledge of its dysregulation in lung cancer. In addition, we review investigations to discover therapeutic targets in the spliceosome and give an overview of inhibitors and modulators of the mRNA splicing process identified so far. Together, this provides insight into the value of targeting the spliceosome as a possible new treatment for lung cancer.
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25
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Integrative reconstruction of cancer genome karyotypes using InfoGenomeR. Nat Commun 2021; 12:2467. [PMID: 33927198 PMCID: PMC8085216 DOI: 10.1038/s41467-021-22671-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 03/23/2021] [Indexed: 02/02/2023] Open
Abstract
Annotation of structural variations (SVs) and base-level karyotyping in cancer cells remains challenging. Here, we present Integrative Framework for Genome Reconstruction (InfoGenomeR)-a graph-based framework that can reconstruct individual SVs into karyotypes based on whole-genome sequencing data, by integrating SVs, total copy number alterations, allele-specific copy numbers, and haplotype information. Using whole-genome sequencing data sets of patients with breast cancer, glioblastoma multiforme, and ovarian cancer, we demonstrate the analytical potential of InfoGenomeR. We identify recurrent derivative chromosomes derived from chromosomes 11 and 17 in breast cancer samples, with homogeneously staining regions for CCND1 and ERBB2, and double minutes and breakage-fusion-bridge cycles in glioblastoma multiforme and ovarian cancer samples, respectively. Moreover, we show that InfoGenomeR can discriminate private and shared SVs between primary and metastatic cancer sites that could contribute to tumour evolution. These findings indicate that InfoGenomeR can guide targeted therapies by unravelling cancer-specific SVs on a genome-wide scale.
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26
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Riess C, Irmscher N, Salewski I, Strüder D, Classen CF, Große-Thie C, Junghanss C, Maletzki C. Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma-backbone or add-on in immune-oncology? Cancer Metastasis Rev 2021; 40:153-171. [PMID: 33161487 PMCID: PMC7897202 DOI: 10.1007/s10555-020-09940-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/26/2020] [Indexed: 12/11/2022]
Abstract
Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.
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Affiliation(s)
- Christin Riess
- Department of Medicine, Clinic III - Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
- University Children's and Adolescents' Hospital, Rostock University Medical Center, Rostock, Germany
| | - Nina Irmscher
- Department of Medicine, Clinic III - Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Inken Salewski
- Department of Medicine, Clinic III - Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Daniel Strüder
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery "Otto Körner", Rostock University Medical Center, Rostock, Germany
| | - Carl-Friedrich Classen
- University Children's and Adolescents' Hospital, Rostock University Medical Center, Rostock, Germany
| | - Christina Große-Thie
- Department of Medicine, Clinic III - Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Christian Junghanss
- Department of Medicine, Clinic III - Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Claudia Maletzki
- Department of Medicine, Clinic III - Hematology, Oncology and Palliative Care, Rostock University Medical Center, Rostock, Germany.
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27
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Xie G, Huang B, Sun Y, Wu C, Han Y. RWSF-BLP: a novel lncRNA-disease association prediction model using random walk-based multi-similarity fusion and bidirectional label propagation. Mol Genet Genomics 2021; 296:473-483. [PMID: 33590345 DOI: 10.1007/s00438-021-01764-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 01/28/2021] [Indexed: 12/13/2022]
Abstract
An increasing number of studies and experiments have demonstrated that long noncoding RNAs (lncRNAs) have a massive impact on various biological processes. Predicting potential associations between lncRNAs and diseases not only can improve our understanding of the molecular mechanisms of human diseases but also can facilitate the identification of biomarkers for disease diagnosis, treatment, and prevention. However, identifying such associations through experiments is costly and demanding, thereby prompting researchers to develop computational methods to complement these experiments. In this paper, we constructed a novel model called RWSF-BLP (a novel lncRNA-disease association prediction model using Random Walk-based multi-Similarity Fusion and Bidirectional Label Propagation), which applies an efficient random walk-based multi-similarity fusion (RWSF) method to fuse different similarity matrices and utilizes bidirectional label propagation to predict potential lncRNA-disease associations. Leave-one-out cross-validation (LOOCV) and 5-fold cross-validation (5-fold-CV) were implemented in the evaluation RWSF-BLP performance. Results showed that, RWSF-BLP has reliable AUCs of 0.9086 and 0.9115 ± 0.0044 under the framework of LOOCV and 5-fold-CV and outperformed other four canonical methods. Case studies on lung cancer and leukemia demonstrated that potential lncRNA-disease associations can be predicted through our method. Therefore, our method can accurately infer potential lncRNA-disease associations and may be a good choice in future biomedical research.
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Affiliation(s)
- Guobo Xie
- School of Computer Science, Guangdong University of Technology, Guangzhou, China
| | - Bin Huang
- School of Computer Science, Guangdong University of Technology, Guangzhou, China
| | - Yuping Sun
- School of Computer Science, Guangdong University of Technology, Guangzhou, China.
| | - Changhai Wu
- School of Computer Science, Guangdong University of Technology, Guangzhou, China
| | - Yuqiong Han
- School of Computer Science, Guangdong University of Technology, Guangzhou, China
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28
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Shilkin ES, Boldinova EO, Stolyarenko AD, Goncharova RI, Chuprov-Netochin RN, Smal MP, Makarova AV. Translesion DNA Synthesis and Reinitiation of DNA Synthesis in Chemotherapy Resistance. BIOCHEMISTRY (MOSCOW) 2021; 85:869-882. [PMID: 33045948 DOI: 10.1134/s0006297920080039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Many chemotherapy drugs block tumor cell division by damaging DNA. DNA polymerases eta (Pol η), iota (Pol ι), kappa (Pol κ), REV1 of the Y-family and zeta (Pol ζ) of the B-family efficiently incorporate nucleotides opposite a number of DNA lesions during translesion DNA synthesis. Primase-polymerase PrimPol and the Pol α-primase complex reinitiate DNA synthesis downstream of the damaged sites using their DNA primase activity. These enzymes can decrease the efficacy of chemotherapy drugs, contribute to the survival of tumor cells and to the progression of malignant diseases. DNA polymerases are promising targets for increasing the effectiveness of chemotherapy, and mutations and polymorphisms in some DNA polymerases can serve as additional prognostic markers in a number of oncological disorders.
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Affiliation(s)
- E S Shilkin
- Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182, Russia
| | - E O Boldinova
- Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182, Russia
| | - A D Stolyarenko
- Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182, Russia
| | - R I Goncharova
- Institute of Genetics and Cytology, National Academy of Sciences of Belarus, Minsk, 220072, Republic of Belarus
| | - R N Chuprov-Netochin
- Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia
| | - M P Smal
- Institute of Genetics and Cytology, National Academy of Sciences of Belarus, Minsk, 220072, Republic of Belarus.
| | - A V Makarova
- Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182, Russia.
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29
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Nambirajan A, Singh V, Bhardwaj N, Mittal S, Kumar S, Jain D. SMARCA4/BRG1-Deficient Non-Small Cell Lung Carcinomas: A Case Series and Review of the Literature. Arch Pathol Lab Med 2021; 145:90-98. [PMID: 33367658 DOI: 10.5858/arpa.2019-0633-oa] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2020] [Indexed: 01/04/2023]
Abstract
CONTEXT.— Somatic mutations in SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or BRG1 (Brahma-related gene 1) loss identifies a subset of non-small cell lung carcinomas (NSCLCs) lacking alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes. Preliminary observations suggest responsiveness to immunotherapy and targeted therapies. OBJECTIVE.— To study BRG1 loss in NSCLCs and elucidate the clinicopathologic profile of such SMARCA4-deficient NSCLCs. DESIGN.— Non-small cell lung carcinomas diagnosed during 6 years were subject to immunohistochemistry for BRG1 and BRM (Brahma). Tumors with BRG1 loss were stained with antibodies against thyroid transcription factor 1 (TTF-1), p40, cytokeratins, hepatocyte paraffin 1 (Hep Par 1), Sal-like protein 4 (SALL4), CD34, SRY-box 2 (SOX2), chromogranin, synaptophysin, p53, integrase interactor 1, ALK, and ROS1. EGFR mutation testing was performed by polymerase chain reaction-based method. RESULTS.— Among 100 NSCLCs tested, 4 cases (4%) showed BRG1 loss. The histology ranged from solid adenocarcinomas (n = 1) to large cell/poorly differentiated carcinomas (n = 3) with clear cell cytology in 2 cases. All showed loss/reduction of BRM with variable cytokeratin and SALL4 expression, and were negative for TTF-1, p40, Hep Par 1, ALK, ROS1, and EGFR mutations. CD34 and SOX2 were negative in all 4 cases. Isolated BRM loss was common (21%), distributed across all NSCLC subtypes including squamous cell carcinomas and a hepatoid adenocarcinoma. CONCLUSIONS.— BRG1 loss occurs in a subset of TTF-1/p40-negative poorly differentiated NSCLCs. Identification and follow-up will clarify the prognosis, diagnostic criteria, and potential for therapeutic personalization.
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Affiliation(s)
- Aruna Nambirajan
- From the Departments of Pathology (Nambirajan, Bhardwaj, Jain, Singh), All India Institute of Medical Sciences, New Delhi, India
| | - Varsha Singh
- From the Departments of Pathology (Nambirajan, Bhardwaj, Jain, Singh), All India Institute of Medical Sciences, New Delhi, India
| | - Nishu Bhardwaj
- From the Departments of Pathology (Nambirajan, Bhardwaj, Jain, Singh), All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Mittal
- and Pulmonary Medicine (Mittal), All India Institute of Medical Sciences, New Delhi, India
| | - Sunil Kumar
- Department of Surgical Oncology, Dr B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India (Kumar)
| | - Deepali Jain
- From the Departments of Pathology (Nambirajan, Bhardwaj, Jain, Singh), All India Institute of Medical Sciences, New Delhi, India
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30
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Park S, Kim TM, Cho SY, Kim S, Oh Y, Kim M, Keam B, Kim DW, Heo DS. Combined blockade of polo-like kinase and pan-RAF is effective against NRAS-mutant non-small cell lung cancer cells. Cancer Lett 2020; 495:135-144. [PMID: 32979462 DOI: 10.1016/j.canlet.2020.09.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 09/11/2020] [Accepted: 09/19/2020] [Indexed: 12/26/2022]
Abstract
NRAS mutation is rarely observed in non-small cell lung cancer (NSCLC) patients, and there are no approved treatments for NRAS-mutant NSCLC. Here, we evaluated the effect of pan-RAF inhibitors on human NRAS-mutant NSCLC cell lines and performed high-throughput screening using human kinome small interfering (si)RNA or CRISPR/Cas9 libraries to identify new targets for combination NSCLC treatment. Our results indicate that human NRAS-mutant NSCLC cells are moderately sensitive to pan-RAF inhibitors. High-throughput kinome screenings further showed that G2/M arrest, particularly following knockdown of polo-like kinase 1 (PLK1), can inhibit the growth of human NRAS-mutant NSCLC cells and those treated with the type II pan-RAF inhibitor LXH254. In addition, treatment with volasertib plus LXH254, resulting in dual blockade of PLK1 and pan-RAF, was found to be more effective than LXH254 monotherapy for inhibiting long-term cell viability, suggesting that this combination therapeutic strategy may lead to promising results in the clinic.
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Affiliation(s)
- Siyeon Park
- Seoul National University Cancer Research Institute, South Korea
| | - Tae Min Kim
- Seoul National University Cancer Research Institute, South Korea; Department of Internal Medicine, Seoul National University Hospital, South Korea.
| | - Sung-Yup Cho
- Seoul National University Cancer Research Institute, South Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, South Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
| | - Soyeon Kim
- Seoul National University Cancer Research Institute, South Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Yumi Oh
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, South Korea
| | - Miso Kim
- Seoul National University Cancer Research Institute, South Korea; Department of Internal Medicine, Seoul National University Hospital, South Korea
| | - Bhumsuk Keam
- Seoul National University Cancer Research Institute, South Korea; Department of Internal Medicine, Seoul National University Hospital, South Korea
| | - Dong-Wan Kim
- Seoul National University Cancer Research Institute, South Korea; Department of Internal Medicine, Seoul National University Hospital, South Korea
| | - Dae Seog Heo
- Seoul National University Cancer Research Institute, South Korea; Department of Internal Medicine, Seoul National University Hospital, South Korea
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31
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Wang J, Xie X, Shi J, He W, Chen Q, Chen L, Gu W, Zhou T. Denoising Autoencoder, A Deep Learning Algorithm, Aids the Identification of A Novel Molecular Signature of Lung Adenocarcinoma. GENOMICS PROTEOMICS & BIOINFORMATICS 2020; 18:468-480. [PMID: 33346087 PMCID: PMC8242334 DOI: 10.1016/j.gpb.2019.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 01/11/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023]
Abstract
Precise biomarker development is a key step in disease management. However, most of the published biomarkers were derived from a relatively small number of samples with supervised approaches. Recent advances in unsupervised machine learning promise to leverage very large datasets for making better predictions of disease biomarkers. Denoising autoencoder (DA) is one of the unsupervised deep learning algorithms, which is a stochastic version of autoencoder techniques. The principle of DA is to force the hidden layer of autoencoder to capture more robust features by reconstructing a clean input from a corrupted one. Here, a DA model was applied to analyze integrated transcriptomic data from 13 published lung cancer studies, which consisted of 1916 human lung tissue samples. Using DA, we discovered a molecular signature composed of multiple genes for lung adenocarcinoma (ADC). In independent validation cohorts, the proposed molecular signature is proved to be an effective classifier for lung cancer histological subtypes. Also, this signature successfully predicts clinical outcome in lung ADC, which is independent of traditional prognostic factors. More importantly, this signature exhibits a superior prognostic power compared with the other published prognostic genes. Our study suggests that unsupervised learning is helpful for biomarker development in the era of precision medicine.
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Affiliation(s)
- Jun Wang
- Department of Thoracic Surgery, Jiangsu Province People's Hospital and the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xueying Xie
- State Key Laboratory of Bioelectronics, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Junchao Shi
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Wenjun He
- State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou 510000, China
| | - Qi Chen
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Liang Chen
- Department of Thoracic Surgery, Jiangsu Province People's Hospital and the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Wanjun Gu
- State Key Laboratory of Bioelectronics, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing 210096, China.
| | - Tong Zhou
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.
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32
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Evolution from adherent to suspension: systems biology of HEK293 cell line development. Sci Rep 2020; 10:18996. [PMID: 33149219 PMCID: PMC7642379 DOI: 10.1038/s41598-020-76137-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 10/22/2020] [Indexed: 01/28/2023] Open
Abstract
The need for new safe and efficacious therapies has led to an increased focus on biologics produced in mammalian cells. The human cell line HEK293 has bio-synthetic potential for human-like production attributes and is currently used for manufacturing of several therapeutic proteins and viral vectors. Despite the increased popularity of this strain we still have limited knowledge on the genetic composition of its derivatives. Here we present a genomic, transcriptomic and metabolic gene analysis of six of the most widely used HEK293 cell lines. Changes in gene copy and expression between industrial progeny cell lines and the original HEK293 were associated with cellular component organization, cell motility and cell adhesion. Changes in gene expression between adherent and suspension derivatives highlighted switching in cholesterol biosynthesis and expression of five key genes (RARG, ID1, ZIC1, LOX and DHRS3), a pattern validated in 63 human adherent or suspension cell lines of other origin.
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33
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Whalley JP, Buchhalter I, Rheinbay E, Raine KM, Stobbe MD, Kleinheinz K, Werner J, Beltran S, Gut M, Hübschmann D, Hutter B, Livitz D, Perry MD, Rosenberg M, Saksena G, Trotta JR, Eils R, Gerhard DS, Campbell PJ, Schlesner M, Gut IG. Framework for quality assessment of whole genome cancer sequences. Nat Commun 2020; 11:5040. [PMID: 33028839 PMCID: PMC7541455 DOI: 10.1038/s41467-020-18688-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 07/22/2020] [Indexed: 11/25/2022] Open
Abstract
Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2. Working with cancer genomes from multiple projects can increase investigative power, but quality of sequences can vary. Here, the authors present a framework for comparing whole genome sequencing quality to help researchers guide downstream analyses and exclude poor quality samples.
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Affiliation(s)
- Justin P Whalley
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Carrer Baldiri i Reixac 4, 08028, Barcelona, Spain.,Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Ivo Buchhalter
- Division of Theoretical Bioinformatics (B080), German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.,Omics IT and Data Management Core Facility (W610), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Division of Applied Bioinformatics (G200), Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Esther Rheinbay
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.,Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, MA, USA
| | | | - Miranda D Stobbe
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Carrer Baldiri i Reixac 4, 08028, Barcelona, Spain
| | - Kortine Kleinheinz
- Division of Theoretical Bioinformatics (B080), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Johannes Werner
- Division of Theoretical Bioinformatics (B080), German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Department of Biological Oceanography, Leibniz Institute of Baltic Sea Research, Seestraße 15, Rostock, Germany
| | - Sergi Beltran
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Carrer Baldiri i Reixac 4, 08028, Barcelona, Spain
| | - Marta Gut
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Carrer Baldiri i Reixac 4, 08028, Barcelona, Spain
| | - Daniel Hübschmann
- Division of Theoretical Bioinformatics (B080), German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.,Department of Pediatric Immunology, Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany.,Computational Oncology, Molecular Diagnostics Program, National Center for Tumor diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Insititute for Stem cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
| | - Barbara Hutter
- Division of Applied Bioinformatics (G200), Cancer Research Centre (DKFZ), Heidelberg, Germany.,Computational Oncology, Molecular Diagnostics Program, National Center for Tumor diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Marc D Perry
- Department of Radiation Oncology, University of California, San Francisco, CA, USA
| | - Mara Rosenberg
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.,Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, MA, USA
| | | | - Jean-Rémi Trotta
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Carrer Baldiri i Reixac 4, 08028, Barcelona, Spain
| | - Roland Eils
- Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Health Data Science Unit, Heidelberg University Hospital and BioQuant, Im Neuenheimer Feld 267, 69120, Heidelberg, Germany
| | - Daniela S Gerhard
- Office of Cancer Genomics, National Cancer Institute, US National Institutes of Health, Bethesda, MD, USA
| | | | - Matthias Schlesner
- Division of Theoretical Bioinformatics (B080), German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Bioinformatics and Omics Data Analytics (B240), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Ivo G Gut
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Carrer Baldiri i Reixac 4, 08028, Barcelona, Spain. .,Universitat Pompeu Fabra (UPF), Barcelona, Spain.
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34
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Cheng S, Ray D, Lee RTH, Naripogu KB, Yusoff PABM, Goh PBL, Liu Y, Suzuki Y, Das K, Chan HS, Wong WK, Chan WH, Chow PKH, Ong HS, Raj P, Soo KC, Tan P, Epstein DM, Rozen SG. A functional network of gastric-cancer-associated splicing events controlled by dysregulated splicing factors. NAR Genom Bioinform 2020; 2:lqaa013. [PMID: 33575575 PMCID: PMC7671336 DOI: 10.1093/nargab/lqaa013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/26/2019] [Accepted: 02/14/2020] [Indexed: 12/11/2022] Open
Abstract
Comprehensive understanding of aberrant splicing in gastric cancer is lacking. We RNA-sequenced 19 gastric tumor–normal pairs and identified 118 high-confidence tumor-associated (TA) alternative splicing events (ASEs) based on high-coverage sequencing and stringent filtering, and also identified 8 differentially expressed splicing factors (SFs). The TA ASEs occurred in genes primarily involved in cytoskeletal organization. We constructed a correlative network between TA ASE splicing ratios and SF expression, replicated it in independent gastric cancer data from The Cancer Genome Atlas and experimentally validated it by knockdown of the nodal SFs (PTBP1, ESRP2 and MBNL1). Each SF knockdown drove splicing alterations in several corresponding TA ASEs and led to alterations in cellular migration consistent with the role of TA ASEs in cytoskeletal organization. We have therefore established a robust network of dysregulated splicing associated with tumor invasion in gastric cancer. Our work is a resource for identifying oncogenic splice forms, SFs and splicing-generated tumor antigens as biomarkers and therapeutic targets.
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Affiliation(s)
- Shanshan Cheng
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, Hubei 430030, China.,Centre for Computational Biology, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.,Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Debleena Ray
- Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Raymond Teck Ho Lee
- Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Kishore Babu Naripogu
- Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | | | - Pamela Bee Leng Goh
- Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Yujing Liu
- Centre for Computational Biology, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.,Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.,Singapore MIT Alliance, 4 Engineering Dr 3, Singapore 117576, Singapore
| | - Yuka Suzuki
- Centre for Computational Biology, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.,Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Kakoli Das
- Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Hsiang Sui Chan
- Department of General Surgery, Gleneagles Medical Centre, 6A Napier Rd, Singapore 258500, Singapore
| | - Wai Keong Wong
- Department of Upper Gastrointestinal & Bariatric Surgery, Singapore General Hospital, 1 Hospital Dr, Singapore 169608, Singapore
| | - Weng Hoong Chan
- Department of Upper Gastrointestinal & Bariatric Surgery, Singapore General Hospital, 1 Hospital Dr, Singapore 169608, Singapore
| | - Pierce Kah-Hoe Chow
- Division of Surgical Oncology, National Cancer Center Singapore, 11 Hospital Dr, Singapore 169610, Singapore.,Department of HPB and Transplant, Singapore General Hospital, 1 Hospital Dr, Singapore 169608, Singapore.,Clinical, Academic & Faculty Affairs, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Hock Soo Ong
- Department of General Surgery, Singapore General Hospital, 1 Hospital Dr, Singapore 169608, Singapore
| | - Prema Raj
- General Surgery, Mount Elizabeth Medical Center, 3 Mount Elizabeth, Singapore 228510, Singapore
| | - Khee Chee Soo
- Division of Surgical Oncology, National Cancer Center Singapore, 11 Hospital Dr, Singapore 169610, Singapore.,Clinical, Academic & Faculty Affairs, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, 21 Lower Kent Ridge Rd, Singapore 119077, Singapore
| | - Patrick Tan
- Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - David M Epstein
- Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
| | - Steven G Rozen
- Centre for Computational Biology, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.,Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
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35
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Zhang Z, Zheng L, Yu Y, Wu J, Yang F, Xu Y, Guo Q, Wu X, Cao S, Cao L, Song X. Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review). Int J Oncol 2020; 56:879-888. [PMID: 32319570 DOI: 10.3892/ijo.2020.4988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 02/07/2020] [Indexed: 11/06/2022] Open
Abstract
Sterile alpha motif and histidine/aspartic acid domain‑containing protein 1 (SAMHD1), the only deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, plays a crucial role in regulating the dynamic balance and ratio of cellular dNTP pools. Furthermore, SAMHD1 has been reported to be involved in the pathological process of several diseases. Homozygous SAMHD1 mutations have been identified in immune system disorders, such as autoimmune disease Aicardi‑Goutières syndrome (AGS), whose primary pathogenesis is associated with the abnormal accumulation and disproportion of dNTPs. SAMHD1 is also considered to be an intrinsic virus‑restriction factor by suppressing the viral infection process, including reverse transcription, replication, packaging and transmission. In addition, SAMHD1 has been shown to promote genome integrity during homologous recombination following DNA damage, thus being considered a promising candidate for oncotherapy applications. The present review summarizes the molecular mechanisms of SAMHD1 regarding the regulation of dNTP homeostasis and DNA damage response. Additionally, its potential effects on tumorigenesis and oncotherapy are reported.
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Affiliation(s)
- Zhou Zhang
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Lixia Zheng
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Yang Yu
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Jinying Wu
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Fan Yang
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Yingxi Xu
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Qiqiang Guo
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Xuan Wu
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Sunrun Cao
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Liu Cao
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Xiaoyu Song
- College of Basic Medical Science, Institute of Translational Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
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36
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Hu Y, Cheng L, Zhong W, Chen M, Zhang Q. Bioinformatics Analysis of Gene Expression Profiles for Risk Prediction in Patients with Septic Shock. Med Sci Monit 2019; 25:9563-9571. [PMID: 31838482 PMCID: PMC6929537 DOI: 10.12659/msm.918491] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Septic shock occurs when sepsis is associated with critically low blood pressure, and has a high mortality rate. This study aimed to undertake a bioinformatics analysis of gene expression profiles for risk prediction in septic shock. Material/Methods Two good quality datasets associated with septic shock were downloaded from the Gene Expression Omnibus (GEO) database, GSE64457 and GSE57065. Patients with septic shock had both sepsis and hypotension, and a normal control group was included. The differentially expressed genes (DEGs) were identified using OmicShare tools based on R. Functional enrichment of DEGs was analyzed using DAVID. The protein-protein interaction (PPI) network was established using STRING. Survival curves of key genes were constructed using GraphPad Prism version 7.0. Each putative central gene was analyzed by receiver operating characteristic (ROC) curves using MedCalc statistical software. Results GSE64457 and GSE57065 included 130 RNA samples derived from whole blood from 97 patients with septic shock and 33 healthy volunteers to obtain 975 DEGs, 455 of which were significantly down-regulated and 520 were significantly upregulated (P<0.05). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified significantly enriched DEGs in four signaling pathways, MAPK, TNF, HIF-1, and insulin. Six genes, WDR82, ASH1L, NCOA1, TPR, SF1, and CREBBP in the center of the PPI network were associated with septic shock, according to survival curve and ROC analysis. Conclusions Bioinformatics analysis of gene expression profiles identified four signaling pathways and six genes, potentially representing molecular mechanisms for the occurrence, progression, and risk prediction in septic shock.
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Affiliation(s)
- Yingchun Hu
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Lingxia Cheng
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Wu Zhong
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Muhu Chen
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Qian Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China (mainland)
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37
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Gao W, Li G, Bian X, Rui Y, Zhai C, Liu P, Su J, Wang H, Zhu C, Du Y, Zheng W, Zheng B, Zhang W, Zhang H, Zhao K, Yang Y, Yu X. Defective modulation of LINE-1 retrotransposition by cancer-associated SAMHD1 mutants. Biochem Biophys Res Commun 2019; 519:213-219. [PMID: 31492497 DOI: 10.1016/j.bbrc.2019.08.155] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 08/29/2019] [Indexed: 11/16/2022]
Abstract
Long interspersed nuclear elements (LINE-1) is now considered as the only active autonomous mobile DNA in humans, LINE-1 retrotransposition activities are associated with and fluctuate during cancer initiation and progression; however, the mechanism underlying the increased LINE-1 activity in cancer is poorly understood. SAMHD1 has been reported to be a potent inhibitor of LINE-1 retrotransposition, and SAMHD1 mutations are frequently associated with cancer development. To gain insights on whether cancer-related SAMHD1 mutants affect LINE-1 activity, we explored the biochemical and cellular properties of some human mutants known correlate with the development of cancer. Most of the tested SAMHD1 cancer-related mutations were defective in LINE-1 inhibition. Interestingly we also found that SAMHD1 mutant K288T was defective for dNTPase activity but showed potent activity against LINE-1 retrotransposition. These findings suggest that LINE-1 inhibition does not depend solely on the dNTPase activity of SAMHD1. In contrast, SAMHD1's ability to inhibit ORF2p-mediated LINE-1 RNP reverse transcription was correlated with SAMHD1-mediated LINE-1 inhibition. Together, our data could also facilitate the deeper understanding for the inhibition of endogenous LINE-1 elements by SAMHD1.
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Affiliation(s)
- Wenying Gao
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Guangquan Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, China
| | - Xuefeng Bian
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Yajuan Rui
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chenyang Zhai
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Panpan Liu
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jiaming Su
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hong Wang
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Chunfeng Zhu
- School of Life Science, Tianjin University, Tianjin, China
| | - Yanjia Du
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Wenwen Zheng
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Baisong Zheng
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wenyan Zhang
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Hui Zhang
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Ke Zhao
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
| | - Yongjun Yang
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
| | - XiaoFang Yu
- The First Hospital of Jilin University, Institute of Virology and AIDS Research & Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China; Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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38
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Camici M, Garcia-Gil M, Pesi R, Allegrini S, Tozzi MG. Purine-Metabolising Enzymes and Apoptosis in Cancer. Cancers (Basel) 2019; 11:cancers11091354. [PMID: 31547393 PMCID: PMC6769685 DOI: 10.3390/cancers11091354] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/03/2019] [Accepted: 09/07/2019] [Indexed: 12/17/2022] Open
Abstract
The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5'-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5'-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.
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Affiliation(s)
- Marcella Camici
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy.
| | - Mercedes Garcia-Gil
- Dipartimento di Biologia, Unità di Fisiologia Generale, Via S. Zeno 31, 56127 Pisa, Italy
| | - Rossana Pesi
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy
| | - Simone Allegrini
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy
| | - Maria Grazia Tozzi
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy
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Blanquart C, Linot C, Cartron PF, Tomaselli D, Mai A, Bertrand P. Epigenetic Metalloenzymes. Curr Med Chem 2019; 26:2748-2785. [PMID: 29984644 DOI: 10.2174/0929867325666180706105903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022]
Abstract
Epigenetics controls the expression of genes and is responsible for cellular phenotypes. The fundamental basis of these mechanisms involves in part the post-translational modifications (PTMs) of DNA and proteins, in particular, the nuclear histones. DNA can be methylated or demethylated on cytosine. Histones are marked by several modifications including acetylation and/or methylation, and of particular importance are the covalent modifications of lysine. There exists a balance between addition and removal of these PTMs, leading to three groups of enzymes involved in these processes: the writers adding marks, the erasers removing them, and the readers able to detect these marks and participating in the recruitment of transcription factors. The stimulation or the repression in the expression of genes is thus the result of a subtle equilibrium between all the possibilities coming from the combinations of these PTMs. Indeed, these mechanisms can be deregulated and then participate in the appearance, development and maintenance of various human diseases, including cancers, neurological and metabolic disorders. Some of the key players in epigenetics are metalloenzymes, belonging mostly to the group of erasers: the zinc-dependent histone deacetylases (HDACs), the iron-dependent lysine demethylases of the Jumonji family (JMJ or KDM) and for DNA the iron-dependent ten-eleven-translocation enzymes (TET) responsible for the oxidation of methylcytosine prior to the demethylation of DNA. This review presents these metalloenzymes, their importance in human disease and their inhibitors.
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Affiliation(s)
- Christophe Blanquart
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
| | - Camille Linot
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France
| | - Pierre-François Cartron
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
| | - Daniela Tomaselli
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
| | - Antonello Mai
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.,Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
| | - Philippe Bertrand
- Réseau Epigénétique du Cancéropôle Grand Ouest, France.,Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 51106, B27, 86073, Poitiers cedex 09, France
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Liang Z, Li X, Chen J, Cai H, Zhang L, Li C, Tong J, Hu W. PRC1 promotes cell proliferation and cell cycle progression by regulating p21/p27-pRB family molecules and FAK-paxillin pathway in non-small cell lung cancer. Transl Cancer Res 2019; 8:2059-2072. [PMID: 35116955 PMCID: PMC8799135 DOI: 10.21037/tcr.2019.09.19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 09/11/2019] [Indexed: 12/12/2022]
Abstract
Background This study aimed to demonstrate the function and molecular mechanism of protein regulator of cytokinesis 1 (PRC1) in the carcinogenesis of non-small cell lung cancer (NSCLC). Methods Bioinformatics analysis was performed. Cell culture and plasmid construction were conducted for cell transfection. mRNA and protein expression, cell proliferation, migration, and cell cycle were detected. Mice models were also constructed. The relationship between PRC1 and the prognosis of NSCLC patients was analyzed. Results PRC1 expression was higher in tumor tissues than adjacent non-tumor tissues (P<0.05). Cells transfected with the high-expression PRC1 plasmid (TOPO-PRC1 group) had the stronger ability of proliferation and migration (P<0.05) along with a lower incidence of stay at the G2/M phase (P<0.05) than the low-expression PRC1 plasmid. Mice models showed tumors obtained from mice in the TOPO-PRC1 group significantly grew faster, larger, and heavier (P<0.05) than the low-expression PRC1 group. Among the 150 NSCLC patients, patients with the higher PRC1 expression were more likely to have lymph node metastasis occur (P<0.05) and progress into an advanced stage (P<0.05), and showed shorter survival (P<0.05). Moreover, the TOPO-PRC1 group had a lower phosphorylation level, and a lower expression of Cip1/p21 (P<0.05) and Kip1/p27 (P<0.01). Conclusions PRC1 could promote cell proliferation and cell cycle progression through FAK-paxillin pathway molecules and the regulation of the phosphorylation level of p21/p27-pRB family molecules. PRC1 might be a new and promising therapeutic target for NSCLC.
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Affiliation(s)
- Zhigang Liang
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
| | - Xinjian Li
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
| | - Jian Chen
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
| | - Haina Cai
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
| | - Liqun Zhang
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
| | - Chenwei Li
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
| | - Jingjie Tong
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
| | - Wentao Hu
- Department of Thoracic Surgery, Ningbo First Hospital, Ningbo 315000, China
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Qiu Z, Li H, Zhang Z, Zhu Z, He S, Wang X, Wang P, Qin J, Zhuang L, Wang W, Xie F, Gu Y, Zou K, Li C, Li C, Wang C, Cen J, Chen X, Shu Y, Zhang Z, Sun L, Min L, Fu Y, Huang X, Lv H, Zhou H, Ji Y, Zhang Z, Meng Z, Shi X, Zhang H, Li Y, Hui L. A Pharmacogenomic Landscape in Human Liver Cancers. Cancer Cell 2019; 36:179-193.e11. [PMID: 31378681 PMCID: PMC7505724 DOI: 10.1016/j.ccell.2019.07.001] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 05/17/2019] [Accepted: 07/01/2019] [Indexed: 12/30/2022]
Abstract
Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Asian People/genetics
- Biomarkers, Tumor/genetics
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/ethnology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Clinical Decision-Making
- Databases, Genetic
- Drug Resistance, Neoplasm/genetics
- Female
- Genetic Heterogeneity
- Genetic Predisposition to Disease
- High-Throughput Nucleotide Sequencing
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/ethnology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, Nude
- Mice, SCID
- Patient Selection
- Pharmacogenomic Testing
- Pharmacogenomic Variants
- Phenotype
- Precision Medicine
- Protein Kinase Inhibitors/pharmacology
- Sorafenib/pharmacology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Zhixin Qiu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Hong Li
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhengtao Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhenfeng Zhu
- Department of Minimally Invasive Therapy, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Sheng He
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
| | - Xujun Wang
- SJTU-Yale Joint Center for Biostatistics, Department of Bioinformatics and Biostatistics, Shanghai Jiaotong University, Shanghai 200240, China
| | - Pengcheng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Jianjie Qin
- Liver Transplantation Center, Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Liping Zhuang
- Department of Minimally Invasive Therapy, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Fubo Xie
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Ying Gu
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Keke Zou
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chao Li
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chun Li
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chenhua Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jin Cen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaotao Chen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yajing Shu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhao Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lulu Sun
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lihua Min
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yong Fu
- Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Xiaowu Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Hui Lv
- SJTU-Yale Joint Center for Biostatistics, Department of Bioinformatics and Biostatistics, Shanghai Jiaotong University, Shanghai 200240, China
| | - He Zhou
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhigang Zhang
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Zhiqiang Meng
- Department of Minimally Invasive Therapy, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 211166, China.
| | - Haibin Zhang
- Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
| | - Yixue Li
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Lijian Hui
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China; Bio-Research Innovation Center Suzhou, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Suzhou, Jiangsu 215121, China.
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Frankiw L, Baltimore D, Li G. Alternative mRNA splicing in cancer immunotherapy. Nat Rev Immunol 2019; 19:675-687. [PMID: 31363190 DOI: 10.1038/s41577-019-0195-7] [Citation(s) in RCA: 179] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2019] [Indexed: 12/12/2022]
Abstract
Immunotherapies are yielding effective treatments for several previously untreatable cancers. Still, the identification of suitable antigens specific to the tumour that can be targets for cancer vaccines and T cell therapies is a challenge. Alternative processing of mRNA, a phenomenon that has been shown to alter the proteomic diversity of many cancers, may offer the potential of a broadened target space. Here, we discuss the promise of analysing mRNA processing events in cancer cells, with an emphasis on mRNA splicing, for the identification of potential new targets for cancer immunotherapy. Further, we highlight the challenges that must be overcome for this new avenue to have clinical applicability.
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Affiliation(s)
- Luke Frankiw
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - David Baltimore
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
| | - Guideng Li
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. .,Suzhou Institute of Systems Medicine, Suzhou, China.
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Guo B, Zheng Q. Using Naïve Bayes Algorithm to Estimate the Response to Drug in Lung Cancer Patients. Comb Chem High Throughput Screen 2019; 21:734-748. [PMID: 30686250 DOI: 10.2174/1386207322666190125151624] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/11/2018] [Accepted: 11/02/2018] [Indexed: 11/22/2022]
Abstract
AIM AND OBJECTIVE Lung cancer is a highly heterogeneous cancer, due to the significant differences in molecular levels, resulting in different clinical manifestations of lung cancer patients there is a big difference. Including disease characterization, drug response, the risk of recurrence, survival, etc. Method Clinical patients with lung cancer do not have yet particularly effective treatment options, while patients with lung cancer resistance not only delayed the treatment cycle but also caused strong side effects. Therefore, if we can sum up the abnormalities of functional level from the molecular level, we can scientifically and effectively evaluate the patients' sensitivity to treatment and make the personalized treatment strategies to avoid the side effects caused by over-treatment and improve the prognosis. RESULT & CONCLUSION According to the different sensitivities of lung cancer patients to drug response, this study screened out genes that were significantly associated with drug resistance. The bayes model was used to assess patient resistance.
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Affiliation(s)
- Baoling Guo
- Department of Oncology, Longyan First Hospital, Affiliated to Fujian Medical University, Longyan, China
| | - Qiuxiang Zheng
- Department of Oncology, Longyan First Hospital, Affiliated to Fujian Medical University, Longyan, China
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The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Exp Mol Med 2019; 51:1-17. [PMID: 31221981 PMCID: PMC6586683 DOI: 10.1038/s12276-019-0230-6] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 12/12/2018] [Indexed: 12/16/2022] Open
Abstract
Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development. The cancer genome atlas (TCGA) project identified 299 genes and 24 pathways/biological processes that drive tumor progression (Cell 173: 371-385 e318, 2018). Of the 299 driver genes, 12 genes are involved in histones, histone methylation, and demethylation. Among these 12 genes, those encoding the histone demethylases JARID1C/KDM5C and UTX/KDM6A were identified as cancer driver genes. Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of α-ketoglutarate, O2-dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases. Studies on oncometabolites suggest that histone demethylases mediate metabolic changes in chromatin structure. We have reviewed the most recent findings regarding cancer-specific metabolic reprogramming and the tumor-suppressive roles of JARID1C/KDM5C and UTX/KDM6A. We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type. Genes involved in the removal of methyl groups from histones associated with DNA can promote or suppress tumor growth depending on the metabolic status of the cancer cell. Hyunsung Park and colleagues at the University of Seoul, South Korea, review current knowledge of two genes encoding histone demethylases which have been identified by The Cancer Genome Atlas (TCGA) project as cancer driver genes. Because these demethylase enzymes rely on cellular metabolites to function, their effect is influenced by metabolic conditions in the tumor microenvironment such as low oxygen. The mechanisms through which changes in histone methylation affect the expression of genes involved in tumor progression remain unknown. Further understanding of how cancer metabolism affects the modification of histones will help guide the development of more effective cancer treatments.
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Small-Molecule Ferroptotic Agents with Potential to Selectively Target Cancer Stem Cells. Sci Rep 2019; 9:5926. [PMID: 30976078 PMCID: PMC6459861 DOI: 10.1038/s41598-019-42251-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 03/22/2019] [Indexed: 02/07/2023] Open
Abstract
Effective management of advanced cancer requires systemic treatment including small molecules that target unique features of aggressive tumor cells. At the same time, tumors are heterogeneous and current evidence suggests that a subpopulation of tumor cells, called tumor initiating or cancer stem cells, are responsible for metastatic dissemination, tumor relapse and possibly drug resistance. Classical apoptotic drugs are less effective against this critical subpopulation. In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species to induce ferroptosis. Interestingly, we find that drug sensitivity is highest in tumor cells with a mesenchymal phenotype. Furthermore, these compounds showed enhanced toxicity towards mesenchymal breast cancer populations with cancer stem cell properties in vitro. In summary, we have identified a new class of small molecule ferroptotic agents that warrant further investigation.
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Malik S, Zafar Paracha R, Khalid M, Nisar M, Siddiqa A, Hussain Z, Nawaz R, Ali A, Ahmad J. MicroRNAs and their target mRNAs as potential biomarkers among smokers and non-smokers with lung adenocarcinoma. IET Syst Biol 2019; 13:69-76. [PMID: 33444474 PMCID: PMC8687273 DOI: 10.1049/iet-syb.2018.5040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/17/2018] [Accepted: 08/06/2018] [Indexed: 01/09/2023] Open
Abstract
Lung adenocarcinoma is one of the major causes of mortality. Current methods of diagnosis can be improved through identification of disease specific biomarkers. MicroRNAs are small non-coding regulators of gene expression, which can be potential biomarkers in various diseases. Thus, the main objective of this study was to gain mechanistic insights into genetic abnormalities occurring in lung adenocarcinoma by implementing an integrative analysis of miRNAs and mRNAs expression profiles in the case of both smokers and non-smokers. Differential expression was analysed by comparing publicly available lung adenocarcinoma samples with controls. Furthermore, weighted gene co-expression network analysis is performed which revealed mRNAs and miRNAs significantly correlated with lung adenocarcinoma. Moreover, an integrative analysis resulted in identification of several miRNA-mRNA pairs which were significantly dysregulated in non-smokers with lung adenocarcinoma. Also two pairs (miR-133b/Protein Kinase C Zeta (PRKCZ) and miR-557/STEAP3) were found specifically dysregulated in smokers. Pathway analysis further revealed their role in important signalling pathways including cell cycle. This analysis has not only increased the authors' understanding about lung adenocarcinoma but also proposed potential biomarkers. However, further wet laboratory studies are required for the validation of these potential biomarkers which can be used to diagnose lung adenocarcinoma.
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Affiliation(s)
- Sumaria Malik
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Rehan Zafar Paracha
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Maryam Khalid
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Maryum Nisar
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Amnah Siddiqa
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Zamir Hussain
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Raheel Nawaz
- School of ComputingMathematics and Digital Technology, Manchester Metropolitan UniversityGM459 Geoffrey Manton BuildingManchesterEngland
| | - Amjad Ali
- Atta‐ur‐Rahman School of Applied Biosciences – ASABNational University of Sciences and Technology (NUST)Sector H‐ 12IslamabadPakistan
| | - Jamil Ahmad
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
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47
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Liu Y, Feng X, Zhao H, Xuan Z, Wang L. A Novel Network-Based Computational Model for Prediction of Potential LncRNA⁻Disease Association. Int J Mol Sci 2019; 20:ijms20071549. [PMID: 30925672 PMCID: PMC6480945 DOI: 10.3390/ijms20071549] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating studies have shown that long non-coding RNAs (lncRNAs) are involved in many biological processes and play important roles in a variety of complex human diseases. Developing effective computational models to identify potential relationships between lncRNAs and diseases can not only help us understand disease mechanisms at the lncRNA molecular level, but also promote the diagnosis, treatment, prognosis, and prevention of human diseases. For this paper, a network-based model called NBLDA was proposed to discover potential lncRNA⁻disease associations, in which two novel lncRNA⁻disease weighted networks were constructed. They were first based on known lncRNA⁻disease associations and topological similarity of the lncRNA⁻disease association network, and then an lncRNA⁻lncRNA weighted matrix and a disease⁻disease weighted matrix were obtained based on a resource allocation strategy of unequal allocation and unbiased consistence. Finally, a label propagation algorithm was applied to predict associated lncRNAs for the investigated diseases. Moreover, in order to estimate the prediction performance of NBLDA, the framework of leave-one-out cross validation (LOOCV) was implemented on NBLDA, and simulation results showed that NBLDA can achieve reliable areas under the ROC curve (AUCs) of 0.8846, 0.8273, and 0.8075 in three known lncRNA⁻disease association datasets downloaded from the lncRNADisease database, respectively. Furthermore, in case studies of lung cancer, leukemia, and colorectal cancer, simulation results demonstrated that NBLDA can be a powerful tool for identifying potential lncRNA⁻disease associations as well.
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Affiliation(s)
- Yang Liu
- College of Computer Engineering & Applied Mathematics, Changsha University, Changsha 410000, China.
- Key Laboratory of Hunan Province for Internet of Things and Information Security, Xiangtan University, Xiangtan 411100, China.
| | - Xiang Feng
- College of Computer Engineering & Applied Mathematics, Changsha University, Changsha 410000, China.
- Key Laboratory of Hunan Province for Internet of Things and Information Security, Xiangtan University, Xiangtan 411100, China.
| | - Haochen Zhao
- Key Laboratory of Hunan Province for Internet of Things and Information Security, Xiangtan University, Xiangtan 411100, China.
| | - Zhanwei Xuan
- Key Laboratory of Hunan Province for Internet of Things and Information Security, Xiangtan University, Xiangtan 411100, China.
| | - Lei Wang
- College of Computer Engineering & Applied Mathematics, Changsha University, Changsha 410000, China.
- Key Laboratory of Hunan Province for Internet of Things and Information Security, Xiangtan University, Xiangtan 411100, China.
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Díaz-Talavera A, Calvo PA, González-Acosta D, Díaz M, Sastre-Moreno G, Blanco-Franco L, Guerra S, Martínez-Jiménez MI, Méndez J, Blanco L. A cancer-associated point mutation disables the steric gate of human PrimPol. Sci Rep 2019; 9:1121. [PMID: 30718533 PMCID: PMC6362072 DOI: 10.1038/s41598-018-37439-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 12/03/2018] [Indexed: 11/30/2022] Open
Abstract
PrimPol is a human primase/polymerase specialized in re-starting stalled forks by repriming beyond lesions such as pyrimidine dimers, and replication-perturbing structures including G-quadruplexes and R-loops. Unlike most conventional primases, PrimPol proficiently discriminates against ribonucleotides (NTPs), being able to start synthesis using deoxynucleotides (dNTPs), yet the structural basis and physiological implications for this discrimination are not understood. In silico analyses based on the three-dimensional structure of human PrimPol and related enzymes enabled us to predict a single residue, Tyr100, as the main effector of sugar discrimination in human PrimPol and a change of Tyr100 to histidine to boost the efficiency of NTP incorporation. We show here that the Y100H mutation profoundly stimulates NTP incorporation by human PrimPol, with an efficiency similar to that for dNTP incorporation during both primase and polymerase reactions in vitro. As expected from the higher cellular concentration of NTPs relative to dNTPs, Y100H expression in mouse embryonic fibroblasts and U2OS osteosarcoma cells caused enhanced resistance to hydroxyurea, which decreases the dNTP pool levels in S-phase. Remarkably, the Y100H PrimPol mutation has been identified in cancer, suggesting that this mutation could be selected to promote survival at early stages of tumorigenesis, which is characterized by depleted dNTP pools.
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Affiliation(s)
- Alberto Díaz-Talavera
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) c/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain
| | - Patricia A Calvo
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) c/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain
| | - Daniel González-Acosta
- Centro Nacional de Investigaciones Oncológicas (CNIO), c/Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Marcos Díaz
- Centro Nacional de Investigaciones Oncológicas (CNIO), c/Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Guillermo Sastre-Moreno
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) c/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain
| | - Luis Blanco-Franco
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) c/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain
| | - Susana Guerra
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) c/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain
| | - Maria I Martínez-Jiménez
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) c/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain
| | - Juan Méndez
- Centro Nacional de Investigaciones Oncológicas (CNIO), c/Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Luis Blanco
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) c/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain.
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Nono AD, Chen K, Liu X. Comparison of different functional prediction scores using a gene-based permutation model for identifying cancer driver genes. BMC Med Genomics 2019; 12:22. [PMID: 30704472 PMCID: PMC6357357 DOI: 10.1186/s12920-018-0452-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Identifying cancer driver genes (CDG) is a crucial step in cancer genomic toward the advancement of precision medicine. However, driver gene discovery is a very challenging task because we are not only dealing with huge amount of data; but we are also faced with the complexity of the disease including the heterogeneity of background somatic mutation rate in each cancer patient. It is generally accepted that CDG harbor variants conferring growth advantage in the malignant cell and they are positively selected, which are critical to cancer development; whereas, non-driver genes harbor random mutations with no functional consequence on cancer. Based on this fact, function prediction based approaches for identifying CDG have been proposed to interrogate the distribution of functional predictions among mutations in cancer genomes (eLS 1–16, 2016). Assuming most of the observed mutations are passenger mutations and given the quantitative predictions for the functional impact of the mutations, genes enriched of functional or deleterious mutations are more likely to be drivers. The promises of these methods have been continually refined and can therefore be applied to increase accuracy in detecting new candidate CDGs. However, current function prediction based approaches only focus on coding mutations and lack a systematic way to pick the best mutation deleteriousness prediction algorithms for usage. Results In this study, we propose a new function prediction based approach to discover CDGs through a gene-based permutation approach. Our method not only covers both coding and non-coding regions of the genes; but it also accounts for the heterogeneous mutational context in cohort of cancer patients. The permutation model was implemented independently using seven popular deleteriousness prediction scores covering splicing regions (SPIDEX), coding regions (MetaLR, and VEST3) and pan-genome (CADD, DANN, Fathmm-MKL coding and Fathmm-MKL noncoding). We applied this new approach to somatic single nucleotide variants (SNVs) from whole-genome sequences of 119 breast and 24 lung cancer patients and compared the seven deleteriousness prediction scores for their performance in this study. Conclusion The new function prediction based approach not only predicted known cancer genes listed in the Cancer Gene Census (CGC), but also new candidate CDGs that are worth further investigation. The results showed the advantage of utilizing pan-genome deleteriousness prediction scores in function prediction based methods. Although VEST3 score, a deleteriousness prediction score for missense mutations, has the best performance in breast cancer, it was topped by CADD and Fathmm-MKL coding, two pan-genome deleteriousness prediction scores, in lung cancer. Electronic supplementary material The online version of this article (10.1186/s12920-018-0452-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alice Djotsa Nono
- Human Genetics Center, UTHealth School of Public Health, Houston, TX, USA
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaoming Liu
- Human Genetics Center, UTHealth School of Public Health, Houston, TX, USA. .,Present Address: USF Genomics, College of Public Health, University of South Florida, Tampa, FL, USA.
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Melzer C, Hass R, Lehnert H, Ungefroren H. RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression. Cells 2019; 8:21. [PMID: 30621237 PMCID: PMC6356296 DOI: 10.3390/cells8010021] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 12/28/2018] [Accepted: 01/02/2019] [Indexed: 02/07/2023] Open
Abstract
RAC1B is an alternatively spliced isoform of the monomeric GTPase RAC1. It differs from RAC1 by a 19 amino acid in frame insertion, termed exon 3b, resulting in an accelerated GDP/GTP-exchange and an impaired GTP-hydrolysis. Although RAC1B has been ascribed several protumorigenic functions such as cell cycle progression and apoptosis resistance, its role in malignant transformation, and other functions driving tumor progression like epithelial-mesenchymal transition, migration/invasion and metastasis are less clear. Insertion of exon 3b endows RAC1B with specific biochemical properties that, when compared to RAC1, encompass both loss-of-functions and gain-of-functions with respect to the type of upstream activators, downstream targets, and binding partners. In its extreme, this may result in RAC1B and RAC1 acting in an antagonistic fashion in regulating a specific cellular response with RAC1B behaving as an endogenous inhibitor of RAC1. In this review, we strive to provide the reader with a comprehensive overview, rather than critical discussions, on various aspects of RAC1B biology in eukaryotic cells.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Hendrik Lehnert
- First Department of Medicine, UKSH, Campus Lübeck, 23538 Lübeck, Germany.
| | - Hendrik Ungefroren
- First Department of Medicine, UKSH, Campus Lübeck, 23538 Lübeck, Germany.
- Department of General and Thoracic Surgery, UKSH, Campus Kiel, 24105 Kiel, Germany.
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