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Lin HY, Jeon AJ, Chen K, Lee CJM, Wu L, Chong SL, Anene-Nzelu CG, Foo RSY, Chow PKH. The epigenetic basis of hepatocellular carcinoma - mechanisms and potential directions for biomarkers and therapeutics. Br J Cancer 2025; 132:869-887. [PMID: 40057667 DOI: 10.1038/s41416-025-02969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/23/2025] [Accepted: 02/20/2025] [Indexed: 05/17/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.
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Affiliation(s)
- Hong-Yi Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Ah-Jung Jeon
- Department of Research and Development, Mirxes, Singapore, Singapore
| | - Kaina Chen
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chang Jie Mick Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
| | - Lingyan Wu
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | - Shay-Lee Chong
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Roger Sik-Yin Foo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore.
- Surgery Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
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Li F, Zhang Y, Wang ZH, Gao S, Fan YC, Wang K. SOCS1 methylation level is associated with prognosis in patients with acute-on-chronic hepatitis B liver failure. Clin Epigenetics 2023; 15:79. [PMID: 37149648 PMCID: PMC10163770 DOI: 10.1186/s13148-023-01495-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 04/28/2023] [Indexed: 05/08/2023] Open
Abstract
BACKGROUND Glucocorticoids could greatly improve the prognosis of patients with acute-on-chronic hepatitis B liver failure (ACHBLF). Suppressor of cytokine signaling (SOCS) 1 methylation has been shown to be associated with mortality in ACHBLF. METHODS Eighty patients with ACHBLF were divided into group glucocorticoid (GC) and group conservative medical (CM). Sixty patients with chronic hepatitis B (CHB), and Thirty healthy controls (HCs) served as control group. SOCS1 methylation levels in peripheral mononuclear cells (PBMCs) was detected by MethyLight. RESULTS SOCS1 methylation levels were significantly higher in patients with ACHBLF than those with CHB and HCs (P < 0.01, respectively). Nonsurvivors showed significantly higher SOCS1 methylation levels (P < 0.05) than survivors in both GC and CM groups in ACHBLF patients. Furthermore, the survival rates of the SOCS1 methylation-negative group were significantly higher than that of the methylation-positive group at 1 month (P = 0.014) and 3 months (P = 0.003) follow-up. Meanwhile, GC group and CM group had significantly lower mortality at 3 months, which may be related to application of glucocorticoid. In the SOCS1 methylation-positive group, the 1-month survival rate was significantly improved, which may be related to GC treatment (P = 0.020). However, no significant difference could be observed between the GC group and CM group in the methylation-negative group (P = 0.190). CONCLUSIONS GC treatment could decrease the mortality of ACHBLF and SOCS1 methylation levels might serve as prognostic marker for favorable response to glucocorticoid treatment.
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Affiliation(s)
- Feng Li
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
| | - Ying Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
| | - Zhao-Hui Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
- Hepatology Institute of Shandong University, Jinan, 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China
- Hepatology Institute of Shandong University, Jinan, 250012, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, Shandong, China.
- Hepatology Institute of Shandong University, Jinan, 250012, China.
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Tao S, Liang S, Zeng T, Yin D. Epigenetic modification-related mechanisms of hepatocellular carcinoma resistance to immune checkpoint inhibition. Front Immunol 2023; 13:1043667. [PMID: 36685594 PMCID: PMC9845774 DOI: 10.3389/fimmu.2022.1043667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/28/2022] [Indexed: 01/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) constitutes most primary liver cancers and is one of the most lethal and life-threatening malignancies globally. Unfortunately, a substantial proportion of HCC patients are identified at an advanced stage that is unavailable for curative surgery. Thus, palliative therapies represented by multi-tyrosine kinase inhibitors (TKIs) sorafenib remained the front-line treatment over the past decades. Recently, the application of immune checkpoint inhibitors (ICIs), especially targeting the PD-1/PD-L1/CTLA-4 axis, has achieved an inspiring clinical breakthrough for treating unresectable solid tumors. However, many HCC patients with poor responses lead to limited benefits in clinical applications, which has quickly drawn researchers' attention to the regulatory mechanisms of immune checkpoints in HCC immune evasion. Evasion of immune surveillance by cancer is attributed to intricate reprogramming modulation in the tumor microenvironment. Currently, more and more studies have found that epigenetic modifications, such as chromatin structure remodeling, DNA methylation, histone post-translational modifications, and non-coding RNA levels, may contribute significantly to remodeling the tumor microenvironment to avoid immune clearance, affecting the efficacy of immunotherapy for HCC. This review summarizes the rapidly emerging progress of epigenetic-related changes during HCC resistance to ICIs and discusses the mechanisms of underlying epigenetic therapies available for surmounting immune resistance. Finally, we summarize the clinical advances in combining epigenetic therapies with immunotherapy, aiming to promote the formation of immune combination therapy strategies.
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Affiliation(s)
- Shengwei Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Shuhang Liang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Taofei Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Dalong Yin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
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Kim M, Delgado E, Ko S. DNA methylation in cell plasticity and malignant transformation in liver diseases. Pharmacol Ther 2023; 241:108334. [PMID: 36535346 PMCID: PMC9841769 DOI: 10.1016/j.pharmthera.2022.108334] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Evan Delgado
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
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Ibrahim J, Peeters M, Van Camp G, Op de Beeck K. Methylation biomarkers for early cancer detection and diagnosis: Current and future perspectives. Eur J Cancer 2023; 178:91-113. [PMID: 36427394 DOI: 10.1016/j.ejca.2022.10.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/11/2022] [Accepted: 10/17/2022] [Indexed: 11/25/2022]
Abstract
The increase in recent scientific studies on cancer biomarkers has brought great new insights into the field. Moreover, novel technological breakthroughs such as long read sequencing and microarrays have enabled high throughput profiling of many biomarkers, while advances in bioinformatic tools have made the possibility of developing highly reliable and accurate biomarkers a reality. These changes triggered renewed interest in biomarker research and provided tremendous opportunities for enhancing cancer management and improving early disease detection. DNA methylation alterations are known to accompany and contribute to carcinogenesis, making them promising biomarkers for cancer, namely due to their stability, frequency and accessibility in bodily fluids. The advent of newer minimally invasive experimental methods such as liquid biopsies provide the perfect setting for methylation-based biomarker development and application. Despite their huge potential, accurate and robust biomarkers for the conclusive diagnosis of most cancer types are still not routinely used, hence a strong need for sustained research in this field is still needed. This review provides a brief exposition of current methylation biomarkers for cancer diagnosis and early detection, including markers already in clinical use as well as various upcoming ones. It also outlines how recent big data and novel technologies will revolutionise the next generation of cancer tests in supplementing or replacing currently existing invasive techniques.
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Affiliation(s)
- Joe Ibrahim
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Marc Peeters
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium; Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Guy Van Camp
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Ken Op de Beeck
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
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Tian Z, Xu C, Yang P, Lin Z, Wu W, Zhang W, Ding J, Ding R, Zhang X, Dou K. Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma. Front Immunol 2022; 13:984728. [PMID: 36189208 PMCID: PMC9520190 DOI: 10.3389/fimmu.2022.984728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.
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Affiliation(s)
- Zelin Tian
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Peijun Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Zhibin Lin
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenlong Wu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an, China
| | - Jian Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Rui Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
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7
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Zanotti S, Boot GF, Coto-Llerena M, Gallon J, Hess GF, Soysal SD, Kollmar O, Ng CKY, Piscuoglio S. The Role of Chronic Liver Diseases in the Emergence and Recurrence of Hepatocellular Carcinoma: An Omics Perspective. Front Med (Lausanne) 2022; 9:888850. [PMID: 35814741 PMCID: PMC9263082 DOI: 10.3389/fmed.2022.888850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/23/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically develops from a background of cirrhosis resulting from chronic inflammation. This inflammation is frequently associated with chronic liver diseases (CLD). The advent of next generation sequencing has enabled extensive analyses of molecular aberrations in HCC. However, less attention has been directed to the chronically inflamed background of the liver, prior to HCC emergence and during recurrence following surgery. Hepatocytes within chronically inflamed liver tissues present highly activated inflammatory signaling pathways and accumulation of a complex mutational landscape. In this altered environment, cells may transform in a stepwise manner toward tumorigenesis. Similarly, the chronically inflamed environment which persists after resection may impact the timing of HCC recurrence. Advances in research are allowing an extensive epigenomic, transcriptomic and proteomic characterization of CLD which define the emergence of HCC or its recurrence. The amount of data generated will enable the understanding of oncogenic mechanisms in HCC from the CLD perspective and provide the possibility to identify robust biomarkers or novel therapeutic targets for the treatment of primary and recurrent HCC. Importantly, biomarkers defined by the analysis of CLD tissue may permit the early detection or prevention of HCC emergence and recurrence. In this review, we compile the current omics based evidence of the contribution of CLD tissues to the emergence and recurrence of HCC.
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Affiliation(s)
- Sofia Zanotti
- Anatomic Pathology Unit, IRCCS Humanitas University Research Hospital, Milan, Italy
| | - Gina F. Boot
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Mairene Coto-Llerena
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - John Gallon
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gabriel F. Hess
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Savas D. Soysal
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Otto Kollmar
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Charlotte K. Y. Ng
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Bern Center for Precision Medicine, Bern, Switzerland
| | - Salvatore Piscuoglio
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
- *Correspondence: Salvatore Piscuoglio
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8
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Yang Z, Chen W, Zhu H, Zhang L, Zhou K, Tang H, Sun R, Huang Y, Xie H, Zheng S, Jia C. Methylation site APC112043544 as a potential biomarker for post-transplant hepatocellular carcinoma recurrence. Future Oncol 2022; 18:2401-2413. [PMID: 35502765 DOI: 10.2217/fon-2021-1608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/13/2022] [Indexed: 11/21/2022] Open
Abstract
Objective: To investigate the prognostic value of DNA methylation of tumor suppressor genes for hepatocellular carcinoma (HCC) recurrence after liver transplantation. Methods: APC gene was selected according to The Cancer Genome Atlas dataset. Tumor tissues and clinical data of 85 HCC patients who received a liver transplantation were retrospectively enrolled and next-generation methylation sequencing was performed. Risk factors were determined using the Cox proportional-hazard-regression model. Results: The APC methylation site (chromosome 5, position 112043544) was an independent predictor of post-transplant HCC recurrence. Patients with hyper-methylated APC112043544 experienced superior recurrence-free survival (p = 0.021) and had a decreased proportion of microvascular invasion (p = 0.017). APC112043544 also predicted recurrence risk in patients beyond selection criteria. Conclusions: APC112043544 methylation may serve as a potential biomarker for post-transplant HCC recurrence.
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Affiliation(s)
- Zhentao Yang
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Wei Chen
- Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Research Center of Diagnosis & Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, 310000, China
| | - Hai Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Road 6, Nanning, 530021, China
| | - Liang Zhang
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Ke Zhou
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Hong Tang
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Ruiqi Sun
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Yiqian Huang
- Department of Pharmacy, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China
| | - Haiyang Xie
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis & Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou, 310000, China
| | - Shusen Zheng
- Department of Surgery, Division of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310000, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis & Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou, 310000, China
| | - Changku Jia
- Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Research Center of Diagnosis & Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, 310000, China
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9
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Kang I, Kim JA, Kim J, Lee JH, Kim MJ, Ahn JK. Hepatitis B virus X protein promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells by regulating SOCS1. BMB Rep 2022. [PMID: 35168698 PMCID: PMC9152579 DOI: 10.5483/bmbrep.2022.55.5.157] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC), a primary type of liver cancer, is one of the leading causes of cancer related deaths worldwide. HCC patients have poor prognosis due to intrahepatic and extrahepatic metastasis. Hepatitis B virus (HBV) infection is one of the major causes of various liver diseases including HCC. Among HBV gene products, HBV X protein (HBx) plays an important role in the development and metastasis of HCC. However, the mechanism of HCC metastasis induced by HBx has not been elucidated yet. In this study, for the first time, we report that HBx interacts with the suppressor of cytokine signaling 1 (SOCS1) which negatively controls NF-κB by degrading p65, a subunit of NF-κB. NF-κB activates the transcription of factors associated with epithelial-mesenchymal transition (EMT), a crucial cellular process associated with invasiveness and migration of cancer cells. Here, we report that HBx physically binds to SOCS1, subsequently prevents the ubiquitination of p65, activates the transcription of EMT transcription factors and enhance cell migration and invasiveness, suggesting a new mechanism of HBV-associated HCC metastasis.
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Affiliation(s)
- Inho Kang
- Department of Microbiology & Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Ji Ae Kim
- Department of Microbiology & Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Jinchul Kim
- Department of Microbiology & Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Ju Hyeon Lee
- Department of Microbiology & Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Mi-jee Kim
- Department of Microbiology & Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Jeong Keun Ahn
- Department of Microbiology & Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea
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10
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Sun D, Gan X, Liu L, Yang Y, Ding D, Li W, Jiang J, Ding W, Zhao L, Hou G, Yu J, Wang J, Yang F, Yuan S, Zhou W. DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334. Cell Death Dis 2022; 13:446. [PMID: 35534462 PMCID: PMC9085879 DOI: 10.1038/s41419-022-04895-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 04/19/2022] [Accepted: 04/28/2022] [Indexed: 12/14/2022]
Abstract
DNA methylation plays a pivotal role in the development and progression of tumors. However, studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. To systematically illustrate the dynamic DNA methylation alternation from premalignant to early-stage liver cancer with the same genetic background, this study enrolled 5 HBV-related patients preceded with liver cirrhosis, pathologically identified as early-stage HCC with dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients were used to measure DNA methylation. Here, we report significant differences in the DNA methylation spectrum among the three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding ability of transcription factor TP53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and relapse-free survival of patients with high ZNF334 expression are significantly longer. Thus, we partly elucidated a sequential alternation of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites. Our study provides a new target and clinical evidence for the early diagnosis and sheds light on the precise treatment of liver cancer.
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Affiliation(s)
- Dapeng Sun
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Xiaojie Gan
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Lei Liu
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Yuan Yang
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Dongyang Ding
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Wen Li
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Junyao Jiang
- grid.428926.30000 0004 1798 2725Center for Health Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou, 510530 China
| | - Wenbin Ding
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Linghao Zhao
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Guojun Hou
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Jian Yu
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Jie Wang
- grid.428926.30000 0004 1798 2725Center for Health Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou, 510530 China
| | - Fu Yang
- grid.73113.370000 0004 0369 1660The department of Medical Genetics, Naval Medical University, Shanghai, 200438 China
| | - Shengxian Yuan
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
| | - Weiping Zhou
- grid.73113.370000 0004 0369 1660The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438 China
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11
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Mechanism of cancer stemness maintenance in human liver cancer. Cell Death Dis 2022; 13:394. [PMID: 35449193 PMCID: PMC9023565 DOI: 10.1038/s41419-022-04848-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 11/08/2022]
Abstract
Primary liver cancer mainly includes the following four types: hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA). Recent studies have indicated that there are differences in cancer stem cell (CSC) properties among different types of liver cancer. Liver cancer stem cells (LCSCs), also called liver tumor-initiating cells, have been viewed as drivers of tumor initiation and metastasis. Many mechanisms and factors, such as mitophagy, mitochondrial dynamics, epigenetic modifications, the tumor microenvironment, and tumor plasticity, are involved in the regulation of cancer stemness in liver cancer. In this review, we analyze cancer stemness in different liver cancer types. Moreover, we further evaluate the mechanism of cancer stemness maintenance of LCSCs and discuss promising treatments for eradicating LCSCs.
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12
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Llovet JM, Pinyol R, Kelley RK, El-Khoueiry A, Reeves HL, Wang XW, Gores GJ, Villanueva A. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. NATURE CANCER 2022; 3:386-401. [PMID: 35484418 PMCID: PMC9060366 DOI: 10.1038/s43018-022-00357-2] [Citation(s) in RCA: 258] [Impact Index Per Article: 86.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/25/2022] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. The poor outcome associated with HCC is dramatically changing due to the advent of effective systemic therapies. Here we discuss the molecular pathogenesis of HCC, molecular classes and determinants of heterogeneity. In addition, effective single-agent and combination systemic therapies involving immunotherapies as standard of care are analyzed. Finally, we propose a flowchart of sequential therapies, explore mechanisms of resistance and address the need for predictive biomarkers.
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Affiliation(s)
- Josep M Llovet
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
| | - Roser Pinyol
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Robin K Kelley
- Helen Diller Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Anthony El-Khoueiry
- Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Helen L Reeves
- Newcastle University Translational and Clinical Research Institute and Newcastle University Centre for Cancer, Medical School, Newcastle Upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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13
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Braghini MR, Lo Re O, Romito I, Fernandez-Barrena MG, Barbaro B, Pomella S, Rota R, Vinciguerra M, Avila MA, Alisi A. Epigenetic remodelling in human hepatocellular carcinoma. J Exp Clin Cancer Res 2022; 41:107. [PMID: 35331312 PMCID: PMC8943959 DOI: 10.1186/s13046-022-02297-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/19/2022] [Indexed: 04/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death. As other heterogeneous solid tumours, HCC results from a unique synergistic combination of genetic alterations mixed with epigenetic modifications.In HCC the patterns and frequencies of somatic variations change depending on the nearby chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutations. Epigenetics refers to heritable states of gene expression without alteration to the DNA sequence itself and, unlike genetic changes, the epigenetic modifications are reversible and affect gene expression more extensively than genetic changes. Thus, studies of epigenetic regulation and the involved molecular machinery are greatly contributing to the understanding of the mechanisms that underline HCC onset and heterogeneity. Moreover, this knowledge may help to identify biomarkers for HCC diagnosis and prognosis, as well as future new targets for more efficacious therapeutic approaches.In this comprehensive review we will discuss the state-of-the-art knowledge about the epigenetic landscape in hepatocarcinogenesis, including evidence on the diagnostic and prognostic role of non-coding RNAs, modifications occurring at the chromatin level, and their role in the era of precision medicine.Apart from other better-known risk factors that predispose to the development of HCC, characterization of the epigenetic remodelling that occurs during hepatocarcinogenesis could open the way to the identification of personalized biomarkers. It may also enable a more accurate diagnosis and stratification of patients, and the discovery of new targets for more efficient therapeutic approaches.
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Affiliation(s)
- Maria Rita Braghini
- Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Viale S. Paolo, 15, 00146, Rome, Italy
| | - Oriana Lo Re
- Department of Translational Stem Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria
| | - Ilaria Romito
- Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Viale S. Paolo, 15, 00146, Rome, Italy
| | - Maite G Fernandez-Barrena
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Barbara Barbaro
- Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Viale S. Paolo, 15, 00146, Rome, Italy
| | - Silvia Pomella
- Department of Paediatric Haematology/Oncology and Cellular and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Rossella Rota
- Department of Paediatric Haematology/Oncology and Cellular and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Manlio Vinciguerra
- Department of Translational Stem Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria
| | - Matias A Avila
- Hepatology Program, CIMA, University of Navarra, Pamplona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Anna Alisi
- Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Viale S. Paolo, 15, 00146, Rome, Italy.
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14
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Desjonqueres E, Campani C, Marra F, Zucman-Rossi J, Nault JC. Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice. Liver Int 2022; 42:492-506. [PMID: 34982503 DOI: 10.1111/liv.15152] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver cancers, accounting for approximately 80% and 15%, respectively. HCC carcinogenesis occurs mostly in cirrhosis and is a complex multi-step process, from precancerous lesions (low-grade and high-grade dysplastic nodules) to progressed HCC. During the different stages of liver carcinogenesis, there is an accumulation of pathological, genetic and epigenetic changes leading to initiation, malignant transformation and finally tumour progression. In contrast, a small subset of HCC occurs in normal liver from the transformation of hepatocellular adenoma (HCA), a benign hepatocellular tumour. The recent molecular classification enables to stratify HCAs according to their risk of complication, in particular malignant transformation, associated with mutations in exon 3 of the catenin beta 1 (CTNNB1) gene. Cholangiocarcinoma (CCA) derives from the multistep malignant transformation of preneoplastic lesions, like biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB), for which a pre-operative diagnosis remains difficult. Different genetic alterations are involved in BilIN and IPNB progression, leading to the development of tubular or intestinal adenocarcinoma. The aims of this review are to describe the main clinical and molecular features of preneoplastic lesions leading to the development of HCC and CCA, their implications in clinical practice and the perspectives for future research.
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Affiliation(s)
- Elvire Desjonqueres
- Service d'hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France.,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
| | - Claudia Campani
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.,Hôpital Européen Georges Pompidou, APHP, Paris, France
| | - Jean-Charles Nault
- Service d'hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France.,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
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15
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Chen F, Wang J, Wu Y, Gao Q, Zhang S. Potential Biomarkers for Liver Cancer Diagnosis Based on Multi-Omics Strategy. Front Oncol 2022; 12:822449. [PMID: 35186756 PMCID: PMC8851237 DOI: 10.3389/fonc.2022.822449] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.
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Affiliation(s)
- Fanghua Chen
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Junming Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yingcheng Wu
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- *Correspondence: Shu Zhang,
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16
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Zhu M, Zhang P, Yu S, Tang C, Wang Y, Shen Z, Chen W, Liu T, Cui Y. Targeting ZFP64/GAL-1 axis promotes therapeutic effect of nab-paclitaxel and reverses immunosuppressive microenvironment in gastric cancer. J Exp Clin Cancer Res 2022; 41:14. [PMID: 34996504 PMCID: PMC8740411 DOI: 10.1186/s13046-021-02224-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/13/2021] [Indexed: 01/03/2023] Open
Abstract
Background Chemoresistance is a main obstacle in gastric cancer (GC) treatment, but its molecular mechanism still needs to be elucidated. Here, we aim to reveal the underlying mechanisms of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resistance in GC. Methods We performed RNA sequencing (RNA-seq) on samples from patients who were resistant or sensitive to nab-paclitaxel, and identified Zinc Finger Protein 64 (ZFP64) as critical for nab-paclitaxel resistance in GC. CCK8, flow cytometry, TUNEL staining, sphere formation assays were performed to investigate the effects of ZFP64 in vitro, while subcutaneous tumor formation models were established in nude mice or humanized mice to evaluate the biological roles of ZFP64 in vivo. Chromatin immunoprecipitation sequencing (CHIP-seq) and double-luciferase reporter gene assay were conducted to reveal the underlying mechanism of ZFP64. Results ZFP64 overexpression was linked with aggressive phenotypes, nab-paclitaxel resistance and served as an independent prognostic factor in GC. As a transcription factor, ZFP64 directly binds to Galectin-1 (GAL-1) promoter and promoted GAL-1 transcription, thus inducing stem-cell like phenotypes and immunosuppressive microenvironment in GC. Importantly, compared to treatment with nab-paclitaxel alone, nab-paclitaxel plus GAL-1 blockade significantly enhanced the anti-tumor effect in mouse models, particularly in humanized mice. Conclusions Our data support a pivotal role for ZFP64 in GC progression by simultaneously promoting cellular chemotherapy resistance and tumor immunosuppression. Treatment with the combination of nab-paclitaxel and a GAL-1 inhibitor might benefit a subgroup of GC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02224-x.
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Affiliation(s)
- Mengxuan Zhu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Center of Evidence-based Medicine, Fudan University, Shanghai, China
| | - Pengfei Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Center of Evidence-based Medicine, Fudan University, Shanghai, China
| | - Shan Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Cheng Tang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yan Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhenbin Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weidong Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Center of Evidence-based Medicine, Fudan University, Shanghai, China.
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Center of Evidence-based Medicine, Fudan University, Shanghai, China.
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17
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Gallon J, Coto-Llerena M, Ercan C, Bianco G, Paradiso V, Nuciforo S, Taha-Melitz S, Meier MA, Boldanova T, Pérez-Del-Pulgar S, Rodríguez-Tajes S, von Flüe M, Soysal SD, Kollmar O, Llovet JM, Villanueva A, Terracciano LM, Heim MH, Ng CKY, Piscuoglio S. Epigenetic priming in chronic liver disease impacts the transcriptional and genetic landscapes of hepatocellular carcinoma. Mol Oncol 2021; 16:665-682. [PMID: 34863035 PMCID: PMC8807355 DOI: 10.1002/1878-0261.13154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/18/2021] [Accepted: 12/02/2021] [Indexed: 01/05/2023] Open
Abstract
Hepatocellular carcinomas (HCCs) usually arise from chronic liver disease (CLD). Precancerous cells in chronically inflamed environments may be 'epigenetically primed', sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD may affect HCC outcomes by influencing the genomic and transcriptomic landscapes of HCC. Analysis of DNA methylation arrays from 10 paired CLD-HCC identified 339 shared dysregulated CpG sites and 18 shared differentially methylated regions compared with healthy livers. These regions were associated with dysregulated expression of genes with relevance in HCC, including ubiquitin D (UBD), cytochrome P450 family 2 subfamily C member 19 (CYP2C19) and O-6-methylguanine-DNA methyltransferase (MGMT). Methylation changes were recapitulated in an independent cohort of nine paired CLD-HCC. High CLD methylation score, defined using the 124 dysregulated CpGs in CLD and HCC in both cohorts, was associated with poor survival, increased somatic genetic alterations and TP53 mutations in two independent HCC cohorts. Oncogenic transcriptional and methylation dysregulation is evident in CLD and compounded in HCC. Epigenetic priming in CLD sculpts the transcriptional landscape of HCC and creates an environment favouring the acquisition of genetic alterations, suggesting that the extent of epigenetic priming in CLD could influence disease outcome.
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Affiliation(s)
- John Gallon
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Switzerland
| | - Mairene Coto-Llerena
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Switzerland.,Institute of Medical Genetics and Pathology, University Hospital Basel, Switzerland
| | - Caner Ercan
- Institute of Medical Genetics and Pathology, University Hospital Basel, Switzerland
| | - Gaia Bianco
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Switzerland
| | - Viola Paradiso
- Institute of Medical Genetics and Pathology, University Hospital Basel, Switzerland
| | - Sandro Nuciforo
- Hepatology Laboratory, Department of Biomedicine, University of Basel, Switzerland
| | - Stephanie Taha-Melitz
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Switzerland
| | - Marie-Anne Meier
- Hepatology Laboratory, Department of Biomedicine, University of Basel, Switzerland
| | - Tujana Boldanova
- Hepatology Laboratory, Department of Biomedicine, University of Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Switzerland
| | | | | | - Markus von Flüe
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Switzerland
| | - Savas D Soysal
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Switzerland
| | - Otto Kollmar
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Switzerland
| | - Josep M Llovet
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Spain.,Liver Cancer Program, Divisions of Liver Diseases and Hematology/Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Augusto Villanueva
- Liver Cancer Program, Divisions of Liver Diseases and Hematology/Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Luigi M Terracciano
- Department of Pathology, Humanitas Clinical and Research Center, IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Markus H Heim
- Hepatology Laboratory, Department of Biomedicine, University of Basel, Switzerland.,Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Switzerland
| | - Charlotte K Y Ng
- Department for BioMedical Research, University of Bern, Switzerland.,SIB, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Salvatore Piscuoglio
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Switzerland.,Institute of Medical Genetics and Pathology, University Hospital Basel, Switzerland
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18
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Zhu H, Zhao H, Xu S, Zhang Y, Ding Y, Li J, Huang C, Ma T. Sennoside A alleviates inflammatory responses by inhibiting the hypermethylation of SOCS1 in CCl 4-induced liver fibrosis. Pharmacol Res 2021; 174:105926. [PMID: 34619344 DOI: 10.1016/j.phrs.2021.105926] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is the consequence of chronic liver injury and is a major challenge to global health. However, successful therapy for liver fibrosis is still lacking. Sennoside A (SA), a commonly used clinical stimulant laxative, is reported to improve hepatic disease, but the underlying mechanisms remain largely elusive. Here, we show for the first time that SA enhanced suppressor of cytokine signaling 1 (SOCS1) expression in a DNA methyltransferase 1 (DNMT1)-dependent manner and thereby attenuated liver fibrosis. Consistently, SA inhibited the expression of the liver fibrogenesis markers α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) and suppressed inflammatory responses in vivo and in vitro. Coculture experiments with macrophages/hepatic stellate cells (HSCs) revealed that SA suppressed HSC proliferation by downregulating proinflammatory cytokines in macrophages. Mechanically, SA promoted the aberrant expression of SOCS1 in liver fibrosis. However, blocking SOCS1 expression weakened the inhibitory effect of SA on HSC proliferation, indicating that SOCS1 may play an important role in mediating the antifibrotic effect of SA. Furthermore, SA inhibited DNMT1-mediated SOCS1 and reduced HSC proliferation by inhibiting inflammatory responses in carbon tetrachloride (CCl4) -induced liver fibrosis.
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Affiliation(s)
- Hong Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Huizi Zhao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Songbing Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Yuan Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Yuhao Ding
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Taotao Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
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19
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Zheng H, Yan Y, Cheng J, Yu S, Wang Y. Association between SOCS3 hypermethylation and HBV-related hepatocellular carcinoma and effect of sex and age: A meta-analysis. Medicine (Baltimore) 2021; 100:e27604. [PMID: 34713837 PMCID: PMC8556007 DOI: 10.1097/md.0000000000027604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 10/01/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Suppressor 3 of cytokine signaling (SOCS3) hypermethylation has been reported to participate in hepatocellular carcinoma (HCC) development and progression, but conflicting results were published. This study aimed to analyze the clinical effects of SOCS3 hypermethylation in HCC and the effects of sex and age on SOCS3 hypermethylation in HCC. METHODS Databases were searched for relevant case-control and cohort studies on SOCS3 hypermethylation in HBV-related HCC. In vitro and in vivo studies and studies of patients with serious comorbidities were excluded. Review Manager 5.2 was used to estimate the effects of the results among the selected studies. Forest plots, sensitivity analysis, and bias analysis for the included studies were also conducted. RESULTS Finally, 8 relevant studies met the inclusion criteria. A significant difference in SOCS3 hypermethylation in HCC was found between tumor and nontumor groups (the odds ratio [OR] = 2.01, 95% confidence interval [CI]: 1.48-2.73, P < .00001; P for heterogeneity = .39, I2 = 5%). The meta-analysis suggested no significant difference in the effect of sex (OR = 1.00, 95% CI: 0.76-1.31, P = .76; P for heterogeneity = .44, I2 = 0%) and age on SOCS3 hypermethylation in HCC (OR = 1.11, 100% CI: 0.78-1.29, P = .03; P for heterogeneity = .14, I2 = 36%). Limited publication bias was observed in this study. CONCLUSION SOCS3 hypermethylation is associated with HBV-related HCC. Sex and age do not affect the association between SOCS3 hypermethylation and HCC. SOCS3 might be a treatment target for HCC.
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Affiliation(s)
- Hairu Zheng
- Department of Physical Examination, the Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yanggang Yan
- Department of Interventional Radiology, the Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jiajia Cheng
- Cancer Center of Minimally Invasive and Comprehensive Therapy, Hainan Cancer Hospital, Haikou, China
| | - Shuyong Yu
- Cancer Center of Minimally Invasive and Comprehensive Therapy, Hainan Cancer Hospital, Haikou, China
| | - Yong Wang
- Department of Interventional Radiology, the Second Affiliated Hospital of Hainan Medical University, Haikou, China
- Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences (No. 2019RU013), Hainan Medical University, China
- Key laboratory of Emergency and Trauma (Hainan Medical University), Ministry of Education, China
- Hainan Clinical Research Center for Acute and Critical Diseases, the Second Affiliated Hospital of Hainan Medical University, China
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20
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Sanceau J, Gougelet A. Epigenetic mechanisms of liver tumor resistance to immunotherapy. World J Hepatol 2021; 13:979-1002. [PMID: 34630870 PMCID: PMC8473495 DOI: 10.4254/wjh.v13.i9.979] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/04/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor, which stands fourth in rank of cancer-related deaths worldwide. The incidence of HCC is constantly increasing in correlation with the epidemic in diabetes and obesity, arguing for an urgent need for new treatments for this lethal cancer refractory to conventional treatments. HCC is the paradigm of inflammation-associated cancer, since more than 80% of HCC emerge consecutively to cirrhosis associated with a vast remodeling of liver microenvironment. In the recent decade, immunomodulatory drugs have been developed and have given impressive results in melanoma and later in several other cancers. In the present review, we will discuss the recent advancements concerning the use of immunotherapies in HCC, in particular those targeting immune checkpoints, used alone or in combination with other anti-cancers agents. We will address why these drugs demonstrate unsatisfactory results in a high proportion of liver cancers and the mechanisms of resistance developed by HCC to evade immune response with a focus on the epigenetic-related mechanisms.
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Affiliation(s)
- Julie Sanceau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris 75006, France
| | - Angélique Gougelet
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris 75006, France.
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21
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Xu YP, Dong ZN, Wang SW, Zheng YM, Zhang C, Zhou YQ, Zhao YJ, Zhao Y, Wang F, Peng R, Tang MC, Bai DS, Huang XY, Guo CY. circHMGCS1-016 reshapes immune environment by sponging miR-1236-3p to regulate CD73 and GAL-8 expression in intrahepatic cholangiocarcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:290. [PMID: 34526098 PMCID: PMC8442376 DOI: 10.1186/s13046-021-02095-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/06/2021] [Indexed: 12/30/2022]
Abstract
Background Accumulating evidence indicates that circRNAs may serve as essential regulators in the progression of several human cancers, but the function and mechanism of circRNAs in intrahepatic cholangiocarcinoma (ICC) are largely unknown. Methods RNA-seq was used to assess differentially expressed circRNAs between 4 ICC and peritumor tissues. Quantitative RT-PCR and in situ hybridization were used to determine the circHMGCS1–016 expression in ICC tissues. The function and mechanism of circHMGCS1–016 were further identified via in vivo experiments. The clinical characteristics and prognostic significance of circHMGCS1–016 were analyzed by a retrospective study. The functions of circHMGCS1–016 were assessed via modifying circRNA expression in ICC cells. Moreover, the molecular mechanisms of circHMGCS1–016 in ICC cells were explored by circRNA precipitation, miRNA immunoprecipitation, SILAC and luciferase reporter assays. Results We identified that compared with peritumor tissues, ICC tissues expressed hsa_circ_0008621 (circHMGCS1–016) high by RNA-seq, which was further identified by qRT-PCR and in situ hybridization. Moreover, the expression of circHMGCS1–016 was revealed to be associated with survival and recurrence of ICC patients. By regulating circHMGCS1–016 expression, we found that elevated circHMGCS1–016 promoted ICC development both in vitro and in vivo. By SILAC and circRNA-pull down, we demonstrated that circHMGCS1–016 induced ICC cell invasion and reshaped the tumor immune microenvironment via the miR-1236-3p/CD73 and GAL-8 axis. In ICC tissues, we uncovered that a high level of circHMGCS1–016 was positively associated with CD73 and GAL-8 expression and negatively related to the CD8+ T cells infiltration, which was further validated by establishing a humanized mouse tumor model. Importantly, we displayed that ICC patients with high levels of circHMGCS1–016 in tumor tissues benefited less from anti-PD1 treatment compared to those with low levels of circHMGCS1–016. Conclusions CircHMGCS1–016 is a forceful contributor in ICC development and immune tolerance via miR-1236-3p/CD73 and GAL-8 axis. CircHMGCS1–016 can be explored as a new potential biomarker and therapeutic target for PD1-resistant ICC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02095-2.
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Affiliation(s)
- Ya-Ping Xu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Ze-Ning Dong
- Xiangya Medical College, Central South University, Changsha, Hunan, 410008, P. R. China.,Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Shanghai, 200032, P. R. China
| | - Si-Wei Wang
- Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Shanghai, 200032, P. R. China
| | - Yi-Min Zheng
- Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Shanghai, 200032, P. R. China
| | - Chi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Subei People's Hospital, Clinical Medical School, Yangzhou University Affiliated Hospital, Yangzhou, China
| | - Ying-Qun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yu-Jie Zhao
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yan Zhao
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Feng Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Rui Peng
- Department of Hepatobiliary and Pancreatic Surgery, Subei People's Hospital, Clinical Medical School, Yangzhou University Affiliated Hospital, Yangzhou, China
| | - Mao-Chun Tang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Dou-Sheng Bai
- Department of Hepatobiliary and Pancreatic Surgery, Subei People's Hospital, Clinical Medical School, Yangzhou University Affiliated Hospital, Yangzhou, China.
| | - Xiao-Yong Huang
- Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Shanghai, 200032, P. R. China.
| | - Chuan-Yong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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22
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Yan Q, Tang Y, He F, Xue J, Zhou R, Zhang X, Luo H, Zhou D, Wang X. Global analysis of DNA methylation in hepatocellular carcinoma via a whole-genome bisulfite sequencing approach. Genomics 2021; 113:3618-3634. [PMID: 34461228 DOI: 10.1016/j.ygeno.2021.08.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 05/01/2021] [Accepted: 08/25/2021] [Indexed: 01/04/2023]
Abstract
Alterations in DNA methylation patterns are considered early events in hepatocellular carcinoma (HCC). However, their mechanism and significance remain to be elucidated. We studied the genome-wide DNA methylation landscape of HCC by applying whole-genome bisulfite sequencing (WGBS) techonlogy. Overall, HCC exhibits a genome-wide hypomethylation pattern. After further annotation, we obtained 590 differentially hypermethylated genes (hyper-DMGs) and 977 differentially hypomethylated genes (hypo-DMGs) from three groups. Hyper-DMGs were mainly involved in ascorbate and alternate metabolism pathways, while hypo-DMGs were mainly involved in focal adhesion. By integrating the DMGs with HCC-related differentially expressed genes (DEGs) and DMGs from the TCGA database, we constructed prognostic model based on thirteen aberrantly methylated DEGs, and verified our prognostic model in GSE14520 dataset. This study compares the patterns of global epigenomic DNA methylation during the development of HCC, focusing on the role of DNA methylation in the early occurrence and development of HCC, providing a direction for future research on its epigenetic mechanism.
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Affiliation(s)
- Qian Yan
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Tang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China; Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fan He
- The First Affiliated Hospital of Guizhou University of Chinese Medicine, Guizhou, China
| | - Jiao Xue
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ruisheng Zhou
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoying Zhang
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huiyan Luo
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Daihan Zhou
- Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Xiongwen Wang
- Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
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23
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Czauderna C, Poplawski A, O Rourke CJ, Castven D, Pérez-Aguilar B, Becker D, Heilmann-Heimbach S, Odenthal M, Amer W, Schmiel M, Drebber U, Binder H, Ridder DA, Schindeldecker M, Straub BK, Galle PR, Andersen JB, Thorgeirsson SS, Park YN, Marquardt JU. Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis. JCI Insight 2021; 6:e146196. [PMID: 34375307 PMCID: PMC8492348 DOI: 10.1172/jci.insight.146196] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
Development of primary liver cancer is a multi-stage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA sequencing analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n=7), low- (n=4) and high-grade (n=9) dysplastic lesions, early (n=5) and progressed (n=3) hepatocellular carcinomas (HCC) synchronously detected in eight HCC patients with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in two independent cohorts comprising 887 HCC. Mitochondrial DNA sequencing was further employed for clonality analyses and indicates multi-clonal origin in the majority of investigated HCC. Alterations in DNA methylation progressively increased from CL to dysplastic lesions and reached a maximum in early HCC. Associated early alterations identified by IPA pathway analyses involved apoptosis, immune regulation and stemness pathways, while late changes centered on cell survival, proliferation and invasion. We further validated putative 23 epi-drivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines.Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for novel therapeutic approaches.
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Affiliation(s)
- Carolin Czauderna
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | - Alicia Poplawski
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg University, Mainz, Germany
| | - Colm J O Rourke
- Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Darko Castven
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | | | - Diana Becker
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | | | | | - Wafa Amer
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Marcel Schmiel
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Uta Drebber
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Harald Binder
- Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Dirk A Ridder
- Department of Pathology, University Medical Center Mainz, Mainz, Germany
| | | | - Beate K Straub
- Department of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Peter R Galle
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
| | - Jesper B Andersen
- Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Snorri S Thorgeirsson
- Laboratory of Experimental Carcinogenesis (LEC), National Cancer Institute, NIH, Bethesda, United States of America
| | - Young Nyun Park
- Department of Pathology, Yonsei University, Seoul, Korea, Republic of
| | - Jens U Marquardt
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany
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24
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Hernandez-Meza G, von Felden J, Gonzalez-Kozlova EE, Garcia-Lezana T, Peix J, Portela A, Craig AJ, Sayols S, Schwartz M, Losic B, Mazzaferro V, Esteller M, Llovet JM, Villanueva A. DNA Methylation Profiling of Human Hepatocarcinogenesis. Hepatology 2021; 74:183-199. [PMID: 33237575 PMCID: PMC8144238 DOI: 10.1002/hep.31659] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue. APPROACH AND RESULTS Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology. CONCLUSIONS Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.
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Affiliation(s)
- Gabriela Hernandez-Meza
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Johann von Felden
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Edgar E. Gonzalez-Kozlova
- Department of Genetics and Genomic Sciences, Cancer Immunology Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Teresa Garcia-Lezana
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Judit Peix
- Translational Research in Hepatic Oncology, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat De Barcelona, Catalonia, Spain
| | - Anna Portela
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Amanda J. Craig
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sergi Sayols
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Institute of Molecular Biology, Mainz, Germany
| | - Myron Schwartz
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bojan Losic
- Department of Genetics and Genomic Sciences, Cancer Immunology Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vincenzo Mazzaferro
- Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy
| | - Manel Esteller
- Josep Carreras Leukemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain,Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.,Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.,Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain
| | - Josep M. Llovet
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Translational Research in Hepatic Oncology, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat De Barcelona, Catalonia, Spain,Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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25
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Role of Nitric Oxide in Gene Expression Regulation during Cancer: Epigenetic Modifications and Non-Coding RNAs. Int J Mol Sci 2021; 22:ijms22126264. [PMID: 34200849 PMCID: PMC8230456 DOI: 10.3390/ijms22126264] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/06/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Nitric oxide (NO) has been identified and described as a dual mediator in cancer according to dose-, time- and compartment-dependent NO generation. The present review addresses the different epigenetic mechanisms, such as histone modifications and non-coding RNAs (ncRNAs), miRNA and lncRNA, which regulate directly or indirectly nitric oxide synthase (NOS) expression and NO production, impacting all hallmarks of the oncogenic process. Among lncRNA, HEIH and UCA1 develop their oncogenic functions by inhibiting their target miRNAs and consequently reversing the inhibition of NOS and promoting tumor proliferation. The connection between miRNAs and NO is also involved in two important features in cancer, such as the tumor microenvironment that includes key cellular components such as tumor-associated macrophages (TAMs), cancer associated fibroblasts (CAFs) and cancer stem cells (CSCs).
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26
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He T, Zhang X, Hao J, Ding S. Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor. Front Physiol 2021; 12:684529. [PMID: 34140896 PMCID: PMC8204087 DOI: 10.3389/fphys.2021.684529] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/28/2021] [Indexed: 12/13/2022] Open
Abstract
The Phosphatase and tensin homolog (PTEN) gene is one of the most important tumor suppressor genes, which acts through its unique protein phosphatase and lipid phosphatase activity. PTEN protein is widely distributed and exhibits complex biological functions and regulatory modes. It is involved in the regulation of cell morphology, proliferation, differentiation, adhesion, and migration through a variety of signaling pathways. The role of PTEN in malignant tumors of the digestive system is well documented. Recent studies have indicated that PTEN may be closely related to many other benign processes in digestive organs. Emerging evidence suggests that PTEN is a potential therapeutic target in the context of several non-neoplastic diseases of the digestive tract. The recent discovery of PTEN isoforms is expected to help unravel more biological effects of PTEN in non-neoplastic digestive diseases.
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Affiliation(s)
- Tianyu He
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Xiaoyun Zhang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
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27
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Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis. Microorganisms 2021; 9:microorganisms9061179. [PMID: 34070716 PMCID: PMC8227491 DOI: 10.3390/microorganisms9061179] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.
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28
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Barcena-Varela M, Lujambio A. The Endless Sources of Hepatocellular Carcinoma Heterogeneity. Cancers (Basel) 2021; 13:2621. [PMID: 34073538 PMCID: PMC8198457 DOI: 10.3390/cancers13112621] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.
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Affiliation(s)
- Marina Barcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Cha S, Jang KL. Hepatitis B virus X protein stimulates cell growth by downregulating p16 levels via PA28γ-mediated proteasomal degradation. J Gen Virol 2021; 101:963-971. [PMID: 32568029 DOI: 10.1099/jgv.0.001461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Proteasomal activator 28 gamma (PA28γ), an essential constituent of the 20S proteasome responsible for ubiquitin-independent degradation of target proteins, is frequently overexpressed in hepatocellular carcinoma. Recently, we have reported that hepatitis B virus (HBV) X protein (HBx) activates PA28γ expression in human hepatocytes via upregulation of p53 levels; however, its role in HBV tumorigenesis remains unknown. Here, we found that HBx-activated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HBx activated the Rb-E2F pathway and stimulated G1/S cell cycle progression, resulting in an increase in cell proliferation. The potential of HBx to induce these effects was reproduced in a 1.2-mer HBV replicon and in in vitro HBV infection systems and was almost completely abolished by either PA28γ knockdown or p16 overexpression, demonstrating the critical role of the PA28γ-mediated p16 degradation in HBV tumorigenesis.
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Affiliation(s)
- Sungkyung Cha
- Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Kyung Lib Jang
- Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
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Mungamuri SK, Nagasuryaprasad K. Epigenetic mechanisms of hepatocellular carcinoma progression: Potential therapeutic opportunities. EPIGENETICS AND METABOLOMICS 2021:279-296. [DOI: 10.1016/b978-0-323-85652-2.00008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Iguchi E, Takai A, Takeda H, Kumagai K, Arasawa S, Eso Y, Shimizu T, Ueda Y, Marusawa H, Seno H. DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis. Sci Rep 2020; 10:21268. [PMID: 33277576 PMCID: PMC7719166 DOI: 10.1038/s41598-020-78151-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/20/2020] [Indexed: 12/24/2022] Open
Abstract
Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.
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Affiliation(s)
- Eriko Iguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Ken Kumagai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Soichi Arasawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kobe University, Hyogo, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
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Nia A, Dhanasekaran R. Genomic Landscape of HCC. CURRENT HEPATOLOGY REPORTS 2020; 19:448-461. [PMID: 33816052 PMCID: PMC8015384 DOI: 10.1007/s11901-020-00553-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/23/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a leading cause of cancer related mortality in the world and it has limited treatment options. Understanding the molecular drivers of HCC is important to develop novel biomarkers and therapeutics. PURPOSE OF REVIEW HCC arises in a complex background of chronic hepatitis, fibrosis and liver regeneration which lead to genomic changes. Here, we summarize studies that have expanded our understanding of the molecular landscape of HCC. RECENT FINDINGS Recent technological advances in next generation sequencing (NGS) have elucidated specific genetic and molecular programs involved in hepatocarcinogenesis. We summarize the major somatic mutations and epigenetic changes have been identified in NGS-based studies. We also describe promising molecular therapies and immunotherapies which target specific genetic and epigenetic molecular events. SUMMARY The genomic landscape of HCC is incredibly complex and heterogeneous. Promising new developments are helping us decipher the molecular drivers of HCC and leading to new therapies.
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Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA. Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg. JHEP Rep 2020; 2:100167. [PMID: 33134907 PMCID: PMC7585149 DOI: 10.1016/j.jhepr.2020.100167] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/22/2020] [Accepted: 07/24/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.
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Key Words
- 5acC, 5-acetylcytosine
- 5fC, 5-formylcytosine
- 5hmC, 5-hydoxymethyl cytosine
- 5mC, 5-methylcytosine
- Acetyl-CoA, acetyl coenzyme A
- BER, base excision repair
- BRD, bromodomain
- CDA, cytidine deaminase
- CGI, CpG island
- CIMP, CGI methylator phenotype
- CTLA-4, cytotoxic T-lymphocyte-associated protein 4
- DNMT, DNA methyltransferase
- DNMTi, DNMT inhibitor
- Epigenetics
- FAD, flavin adenine dinucleotide
- HAT, histone acetyltransferases
- HCC, hepatocellular carcinoma
- HDAC, histone deacetylase
- HDACi, HDAC inhibitor
- HDM, histone demethylase
- HMT, histone methyltransferase
- Hepatocellular carcinoma
- KMT, lysine methyltransferase
- LSD/KDM, lysine specific demethylases
- NAFLD, non-alcoholic fatty liver disease
- NK, natural killer
- NPC, nasopharyngeal carcinoma
- PD-L1, programmed cell death ligand-1
- PD1, programmed cell death protein 1
- PHD, plant homeodomain
- PTM, post-translational modification
- SAM, S-adenosyl-L-methionine
- TDG, thymidine-DNA-glycosylase
- TERT, telomerase reverse transcriptase
- TET, ten-eleven translocation
- TME, tumour microenvironment
- TSG, tumour suppressor gene
- Therapy
- UHRF1, ubiquitin like with PHD and ring finger domains 1
- VEGF, vascular endothelial growth factor
- ncRNAs, non-coding RNAs
- α-KG, α-ketoglutarate
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Affiliation(s)
- Maite G. Fernández-Barrena
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - María Arechederra
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Leticia Colyn
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
| | - Carmen Berasain
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Matias A. Avila
- Hepatology Program CIMA, University of Navarra, Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
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SEPT9 Gene Methylation as a Noninvasive Marker for Hepatocellular Carcinoma. DISEASE MARKERS 2020; 2020:6289063. [PMID: 33178361 PMCID: PMC7647768 DOI: 10.1155/2020/6289063] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 05/15/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023]
Abstract
Background Early detection appears to be the most effective approach to improve the overall survival of patients with hepatocellular carcinoma (HCC). We evaluated the potential performance of plasma SEPT9 methylation (mSEPT9) as a noninvasive biomarker for the diagnosis of patients with HCC. Methods A total of 373 subjects were included, and the group consisted of 104 HCC patients, 95 with an at-risk disease, and 174 healthy controls (HC). The methylation of mSEPT9 was determined using methylation-specific fluorescence quantitative PCR. The diagnostic performance of plasma mSEPT9 for HCC was assessed in a single-blind manner. Results The receiver operating characteristic (ROC) curve showed that plasma mSEPT9 can be used to detect and discriminate HCC with an area under the ROC curve (AUROC) of 0.961, a sensitivity of 82.7%, and specificity of 96.0% from HC. These results showed that plasma mSEPT9 had better diagnostic performance than serum alpha fetoprotein (AFP) (AUROC 0.881, sensitivity 57.7%, and specificity 98.3%). Similar results were noted in the detection of early-stage HCC. When combined with serum AFP, the sensitivity increased to 91.3% and 87.7% for the detection of HCC and early-stage HCC,respectively. Notably, the levels of plasma mSEPT9 dramatically decreased after surgery (P = 0.001). Conclusions Plasma SEPT9 methylation might serve as a useful and noninvasive biomarker for the diagnosis of HCC and can be used to evaluate the therapeutic efficacy of HCC treatment.
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Xu G, Zhou X, Xing J, Xiao Y, Jin B, Sun L, Yang H, Du S, Xu H, Mao Y. Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma. Cancer Cell Int 2020; 20:547. [PMID: 33292241 PMCID: PMC7653745 DOI: 10.1186/s12935-020-01638-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
Background RAS association domain family protein 1A (RASSF1A) promoter hypermethylation is suggested to be linked to hepatocellular carcinoma (HCC), but the results remained controversial. Methods We evaluated how RASSF1A promoter hypermethylation affects HCC risk and its clinicopathological characteristics through meta-analysis. Data on DNA methylation in HCC and relevant clinical data were also collected based on The Cancer Genome Atlas (TCGA) database to investigate the prognostic role of RASSF1A promoter hypermethylation in HCC. Results Forty-four articles involving 4777 individuals were enrolled in the pooled analyses. The RASSF1A promoter methylation rate was notably higher in the HCC cases than the non-tumor cases and healthy individuals, and was significantly related to hepatitis B virus (HBV) infection-positivity and large tumor size. Kaplan–Meier survival analysis revealed that HCC cases with RASSF1A promoter hypermethylation had worse outcomes. Receiver operating characteristic curves confirmed that RASSF1A promoter methylation may be a marker of HCC-related prognoses. Conclusions RASSF1A promoter hypermethylation is a promising biomarker for the diagnosis of HCC from tissue and peripheral blood, and is an emerging therapeutic target against HCC.
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Affiliation(s)
- Gang Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xiaoxiang Zhou
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Jiali Xing
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yao Xiao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Lejia Sun
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, 100730, China.
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Association of RASSF1A hypermethylation with risk of HBV/HCV-induced hepatocellular carcinoma: A meta-analysis. Pathol Res Pract 2020; 216:153099. [PMID: 32853942 DOI: 10.1016/j.prp.2020.153099] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/19/2020] [Accepted: 03/07/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Researchers have discovered a large number of DNA methylation patterns in human cancer. These cancer-specific methylation patterns can provide information for the diagnosis, treatment, and prognosis of cancer. Methylation studies can find new biomarkers based on epigenetic analysis and apply these biomarkers to clinical oncology. Many studies on the association between RAASF1A methylation status and susceptibility to hepatitis B virus (HBV)/hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) have reached controversial conclusions. Hence, the current review comprehensively assessed the correlation between Ras association domain family 1A (RASSF1A) methylation and the risk of the HCV/HBV-induced HCC. METHODS The appropriated publications were extracted in EMBASE, PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases using STATA 5.0 software. The odds ratios (ORs) with 95 % confidence interval (95 % CI) of RASSF1A methylation were computed. RESULTS A total of 1015 HBV/HCV-related HCC samples, 124 non-HBV/HCV-related HCC (NBNC-HCC) samples, and 1225 nontumorous controls were extracted and examined in this research. The frequency of the methylated RASSF1A in the HBV/HCV-related tumor cases displayed a significantly increased OR compared with the overall nontumor samples (OR = 19.372, 95 % CI = 11.060-33.931, P = 0.000). The frequency of the methylated RASSF1A in HBV/HCV-related neoplasm cases displayed a significantly increased OR compared with the non-HBV/HCV-related neoplasm (NBNC-neoplasm) samples (OR = 2.150, 95 % CI = 1.398-3.308, P = 0.000). Compared with normal, chronic hepatitis B or C, cirrhosis, and paracancerous samples, the pooled OR of the RASSF1A promoter methylation in the HBV/HCV-induced HCC samples was 62.785(95 % CI = 35.224-111.909), 25.07 (95 % CI = 13.85-45.36), 6.89 (95 % CI = 3.33-14.264) and 9.02 (95 % CI = 0.91-89.80), respectively. The rate of RASSF1A hypermethylation was robustly correlated with tumor size and vascular invasion, and the pooled OR was 0.346 (95 % CI = 0.210 - 0.569) and 0.081 (95 % CI = 0.022 - 0.303), respectively. CONCLUSION Results showed robust associations between RASSF1A gene methylation in promoter region and enhanced HBV/HCV-related HCC susceptibility, thereby revealing that RASSF1A methylation status may serve as an important indicator for HCC oncogenesis.
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Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, typically develops on the background of chronic liver disease and is an aggressive disease with dismal prognosis. Studies using next-generation sequencing of multiple regions of the same tumour nodule suggest different patterns of HCC evolution and confirm the high molecular heterogeneity in a subset of patients. Different hypotheses have been proposed to explain tumour evolution, including clonal selection or neutral and punctuated acquisition of genetic alterations. In parallel, data indicate a fundamental contribution of nonmalignant cells of the tumour microenvironment to cancer clonal evolution. Delineating these dynamics is crucial to improve the treatment of patients with HCC, and particularly to help understand how HCC evolution drives resistance to systemic therapies. A number of new minimally invasive techniques, such as liquid biopsies, could help track cancer evolution in HCC. These tools might improve our understanding of how systemic therapies affect tumour clonal composition and could facilitate implementation of real-time molecular monitoring of patients with HCC.
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DNA methylation of SOCS1/2/3 predicts hepatocellular carcinoma recurrence after liver transplantation. Mol Biol Rep 2020; 47:1773-1782. [PMID: 32006198 DOI: 10.1007/s11033-020-05271-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023]
Abstract
DNA methylation status of SOCS1/SOCS2/SOCS3 is intensely involved in the development and progression of hepatocellular carcinoma (HCC). This study explored its prognostic value for HCC recurrence after liver transplantation (LT). Clinical data from 62 HCC patients who underwent LT at our centre were retrospectively collected. The SOCS1/2/3 methylation level were determined using next generation sequencing. Overall, 244 methylated sites at the SOCS1/2/3 promoter were identified. Multivariate analysis yielded the methylated sites SOCS2-1-90 (Chromosome 12, Position 93963982; HR 0.386, 95% CI 0.149-0.998) and SOCS1-1-68 (Chromosome 16, Position 11350699; HR 4.376, 95% CI 1.324-14.459) as independent predictors of post-LT HCC recurrence. Patients were divided into highly- and lowly methylated groups according to the median SOCS1-1-68 (0.95%) and SOCS2-1-90 (1.05%) methylation levels. Highly methylated SOCS2-1-90 was associated with significantly lower AFP levels (P = 0.008), decreased proportion of maximal tumour size > 8 cm (P = 0.02), and better pathological grading (P = 0.06). Conversely, patients in the highly methylated SOCS1-1-68 group had higher AFP levels (P = 0.043). Kaplan-Meier analyses revealed that patients with highly methylated SOCS2-1-90 had increased recurrence free survival (RFS) and overall survival (OS) rates when compared with those with lowly methylated SOCS2-1-90 (P = 0.0041 and 0.012, respectively). Nevertheless, the correlation between methylated SOCS1-1-68 and cumulative recurrence rates was less pronounced (P = 0.098). Subgroup analyses demonstrated that patients meeting the Milan criteria, UCSF criteria, Metroticket 2.0 Model or Hangzhou criteria with highly methylated SOCS2-1-90 had the best RFS rates. DNA methylation of SOCS2-1-90 is a novel biomarker for predicting post-transplant HCC recurrence.
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Zhang C, Ge S, Wang J, Jing X, Li H, Mei S, Zhang J, Liang K, Xu H, Zhang X, Zhang C. Epigenomic profiling of DNA methylation for hepatocellular carcinoma diagnosis and prognosis prediction. J Gastroenterol Hepatol 2019; 34:1869-1877. [PMID: 31038805 DOI: 10.1111/jgh.14694] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 03/31/2019] [Accepted: 04/23/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM DNA hypermethylation has emerged as a novel molecular biomarker for the diagnosis and prognosis prediction of many cancers. We aimed to identify clinically useful biomarkers regulated by DNA methylation in hepatocellular carcinoma (HCC). METHODS Genome-wide methylation analysis in HCCs and paired noncancerous tissues was performed using an Illumina Infinium HumanMethylation 450K BeadChip array. Methylation-specific polymerase chain reaction and pyrosequencing were used to validate the methylation status of selected genes in 100 paired HCCs and noncancerous samples. RESULTS A total of 97 027 (20.0%) out of 485 577 CpG sites significantly were differed between HCC and noncancerous tissues. Among all the significant CpG sites, 48.8% are hypermethylated and 51.2% are hypomethylated in HCCs. Multiple signaling pathways (AMP-activated protein kinase, estrogen, and adipocytokine) involved in gene methylation were identified in HCC. FES was selected for further analysis based on its high level of methylation confirmed by polymerase chain reaction and pyrosequencing. The result showed that FES hypermethylation was correlated with tumor size (0.001), serum alpha fetoprotein (0.023), and tumor differentiation (0.006). FES protein was significantly downregulated in 51/100 (51%) HCCs, and 94.12% (48/51) of them were due to promoter hypermethylation. Both FES hypermethylation and protein downregulation were associated with the progression-free survival and overall survival of HCC patients. Overexpressed and knockdown of FES confirmed its inhibitory effect on the proliferation and migration of HCC cells. CONCLUSIONS We identified many new differentially methylated CpGs in HCCs and demonstrate that FES functions as a tumor suppressor gene in HCC and its methylation status could be used as an indicator for prognosis of HCC.
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Affiliation(s)
- Cheng Zhang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Shuang Ge
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Jun Wang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Xiaotong Jing
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | | | - Shuyu Mei
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Juan Zhang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Ke Liang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Hui Xu
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Xiaoying Zhang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Cuijuan Zhang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
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Cozma A, Fodor A, Vulturar R, Sitar-Tăut AV, Orăşan OH, Mureşan F, Login C, Suharoschi R. DNA Methylation and Micro-RNAs: The Most Recent and Relevant Biomarkers in the Early Diagnosis of Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2019; 55:medicina55090607. [PMID: 31546948 PMCID: PMC6780418 DOI: 10.3390/medicina55090607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 09/08/2019] [Accepted: 09/08/2019] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a frequently encountered cancer type, and its alarming incidence is explained by genetic and epigenetic alterations. Epigenetic changes may represent diagnostic and prognostic biomarkers of HCC. In this review we discussed deoxyribonucleic acid (DNA) hypomethylation, DNA hypermethylation, and aberrant expression of small non-coding ribonucleic acid (RNA), which could be useful new biomarkers in the early diagnosis of HCC. We selected the articles on human subjects published in English over the past two years involving diagnostic markers detected in body fluids, cancer diagnosis made on histopathological exam, and a control group of those with benign liver disease or without liver disease. These biomarkers need further investigation in clinical trials to develop clinical applications for early diagnosis and management of HCC.
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Affiliation(s)
- Angela Cozma
- Internal Medicine Department, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Adriana Fodor
- Department of Diabetes and Metabolic Diseases, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Romana Vulturar
- Department of Cell Biology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Adela-Viviana Sitar-Tăut
- Internal Medicine Department, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Olga Hilda Orăşan
- Internal Medicine Department, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Flaviu Mureşan
- Department of Surgery, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Cezar Login
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Ramona Suharoschi
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania.
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Bharali D, Banerjee BD, Bharadwaj M, Husain SA, Kar P. Expression Analysis of MicroRNA-21 and MicroRNA-122 in Hepatocellular Carcinoma. J Clin Exp Hepatol 2019; 9:294-301. [PMID: 31360021 PMCID: PMC6637083 DOI: 10.1016/j.jceh.2018.07.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 07/07/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVE Hepatocellular carcinoma (HCC) is a multistep process starting from chronic hepatitis (CH) that progress through cirrhosis to HCC. The expression level of microRNA (miRNA) was found to be deregulated in HCC. The study was designed to find out whether the expression level of miR-21 and miR-122 was deregulated in HCC compared to controls without HCC. METHODS Real-time quantitative polymerase chain reaction was performed to find out the miRNA expression level using Ct value followed by statistical analysis where P value ≤ 0.05 was considered as significant. RESULTS Overexpression of miR-21 and miR-122 in HCC was detected. All changes in the expression level of miR-21 and miR-122 were due to HCC compared with healthy control, CH, and liver cirrhosis. Hence miR-21 and miR-122 are suitable to differentiate HCC with an efficient diagnostic power of sensitivity, specificity, and expression level, but they might not have any role in patients' survival. CONCLUSION miR-21 and miR-122 could be considered as potential markers of HCC screening molecule in addition to other approved markers. However the current study is limited to expression levels of miRNAs from serum; therefore, it needs further validated study in a large group of population to fulfill all the criteria of a biomarker.
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Affiliation(s)
- Dipu Bharali
- Department of Medicine, Maulana Azad Medical College, New Delhi, 02, India
| | - Basu D. Banerjee
- Department of Biochemistry, University College of Medical Sciences, Dilshad Graden, Delhi, 65, India
| | - Mausumi Bharadwaj
- Division of Molecular Genetics, National Institute Cancer Prevention and Research, Noida, UP, India
| | - Syed A. Husain
- Department of Biosciences, Jamia Millia Islamia University, New Delhi, India
| | - Premashis Kar
- Department of Medicine, Maulana Azad Medical College, New Delhi, 02, India
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Pasha HF, Mohamed RH, Radwan MI. RASSF1A and SOCS1 genes methylation status as a noninvasive marker for hepatocellular carcinoma. Cancer Biomark 2019; 24:241-247. [DOI: 10.3233/cbm-181638] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Heba F. Pasha
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Randa H. Mohamed
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mohamed I. Radwan
- Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Finianos A, Matar CF, Taher A. Hepatocellular Carcinoma in β-Thalassemia Patients: Review of the Literature with Molecular Insight into Liver Carcinogenesis. Int J Mol Sci 2018; 19:ijms19124070. [PMID: 30562917 PMCID: PMC6321074 DOI: 10.3390/ijms19124070] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 12/08/2018] [Accepted: 12/11/2018] [Indexed: 12/18/2022] Open
Abstract
With the continuing progress in managing patients with thalassemia, especially in the setting of iron overload and iron chelation, the life span of these patients is increasing, while concomitantly increasing incidences of many diseases that were less likely to show when survival was rather limited. Hepatocellular carcinoma (HCC) is a major life-threatening cancer that is becoming more frequently identified in this population of patients. The two established risk factors for the development of HCC in thalassemia include iron overload and viral hepatitis with or without cirrhosis. Increased iron burden is becoming a major HCC risk factor in this patient population, especially in those in the older age group. As such, screening thalassemia patients using liver iron concentration (LIC) measurement by means of magnetic resonance imaging (MRI) and liver ultrasound is strongly recommended for the early detection of iron overload and for implementation of early iron chelation in an attempt to prevent organ-damaging iron overload and possibly HCC. There remain lacking data on HCC treatment outcomes in patients who have thalassemia. However, a personalized approach tailored to each patient’s comorbidities is essential to treatment success. Multicenter studies investigating the long-term outcomes of currently available therapeutic options in the thalassemia realm, in addition to novel HCC therapeutic targets, are needed to further improve the prognosis of these patients.
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Affiliation(s)
- Antoine Finianos
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon.
| | - Charbel F Matar
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon.
| | - Ali Taher
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon.
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Liu Y, Zhu H, Zhang Z, Tu C, Yao D, Wen B, Jiang R, Li X, Yi P, Zhan J, Hu J, Ding J, Jiang L, Zhang F. Effects of a single transient transfection of Ten-eleven translocation 1 catalytic domain on hepatocellular carcinoma. PLoS One 2018; 13:e0207139. [PMID: 30551127 PMCID: PMC6294611 DOI: 10.1371/journal.pone.0207139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 10/25/2018] [Indexed: 12/22/2022] Open
Abstract
Tumor suppressor genes (TSGs), including Ten-eleven translocation 1 (TET1), are hypermethylated in hepatocellular carcinoma (HCC). TET1 catalytic domain (TET1-CD) induces genome-wide DNA demethylation to activate TSGs, but so far, anticancer effects of TET1-CD are unclear. Here we showed that after HCC cells were transiently transfected with TET1-CD, the methylation levels of TSGs, namely APC, p16, RASSF1A, SOCS1 and TET1, were distinctly reduced, and their mRNA levels were significantly increased and HCC cells proliferation, migration and invasion were suppressed, but the methylation and mRNA levels of oncogenes, namely C-myc, Bmi1, EMS1, Kpna2 and c-fos, were not significantly change. Strikingly, HCC subcutaneous xenografts in nude mice remained to be significantly repressed even 54 days after transient transfection of TET1-CD. So, transient transfection of TET1-CD may be a great advance in HCC treatment due to its activation of multiple TSGs and persistent anticancer effects.
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Affiliation(s)
- Yuying Liu
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Hui Zhu
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Zhenxue Zhang
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Changchun Tu
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Dongyuan Yao
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Bin Wen
- The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Ru Jiang
- Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, P.R. China
| | - Xing Li
- Gannan Medical University, Ganzhou, Jiangxi, P.R. China
| | - Pengfei Yi
- Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi, P.R. China
| | - Jiejie Zhan
- Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi, P.R. China
| | - Jiaping Hu
- The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Jianwu Ding
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Liping Jiang
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Fanglin Zhang
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi, P.R. China
- * E-mail:
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Zhou Y, Wang XB, Qiu XP, Shuai Zhang, Wang C, Zheng F. CDKN2A promoter methylation and hepatocellular carcinoma risk: A meta-analysis. Clin Res Hepatol Gastroenterol 2018; 42:529-541. [PMID: 30143452 DOI: 10.1016/j.clinre.2017.07.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 07/17/2017] [Accepted: 07/28/2017] [Indexed: 02/04/2023]
Abstract
AIM Lots of studies have explored cyclin-dependent kinase inhibitor 2A (CDKN2A) promoter methylation in hepatocellular carcinoma (HCC), but the established results were controversial. Hence, we conducted the meta-analysis to comprehensively investigate the association between CDKN2A promoter methylation and HCC risk. METHODS A comprehensive search was implemented through searching PubMed, Web of Science and Embase. Associations of CDKN2A promoter methylation with HCC risk, clinicopathological features, and CDKN2A expression were assessed by the pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Subgroup analyses and meta-regression were served for exploring the potential sources of heterogeneity. RESULTS A total of 59 articles including 3067 cases and 2951 controls were incorporated in this meta-analysis. Overall, we observed a high CDKN2A promoter methylation rate (58.18%) in HCC and a significant association between the methylation and HCC risk (OR, 7.07; 95% CI, 5.67-8.80). Furthermore, CDKN2A promoter methylation was robustly associated with decreased mRNA (OR, 13.89; 95% CI, 5.44-35.45) and protein (OR, 48.19; 95% CI, 5.56-417.29). In addition, we found the methylation was related with HBV infection (OR, 3.31; 95% CI, 1.47-7.47), HCV infection (OR, 2.76; 95% CI, 1.80-4.23), cirrhosis status (OR, 1.57; 95% CI, 1.01-2.44) and older age (OR, 1.83; 95% CI, 1.14-2.94). CONCLUSIONS Our results indicated that CDKN2A promoter methylation was associated with an enhancive HCC risk and played a crucial role in the process of HCC with a potential value to being a triage marker for HCC.
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Affiliation(s)
- Ye Zhou
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Xue-Bin Wang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Xue-Ping Qiu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Shuai Zhang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Chen Wang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China
| | - Fang Zheng
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei, China.
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46
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Mekky MA, Salama RH, Abdel-Aal MF, Ghaliony MA, Zaky S. Studying the frequency of aberrant DNA methylation of APC, P14, and E-cadherin genes in HCV-related hepatocarcinogenesis. Cancer Biomark 2018; 22:503-509. [PMID: 29865038 DOI: 10.3233/cbm-171156] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Data about the molecular pathogenesis of hepatitis C-related hepatocellular carcinoma (HCC) are still challenging. OBJECTIVES Therefore, we tried to investigate the epigenetic study of three nominated genes (APC, P14, and E-cadherin) in the pathogenesis of HCV-related HCC in Egyptian. METHODS Between March 2016 and March 2017, the DNA methylation, and quantification using (epigenetic ELISA kit) for E-cadherin, APC, and P14 genes were studied in three groups of patients: HCV related liver cirrhosis without HCC group (LC-group; n= 20), HCC on top of HCV-related cirrhosis (HCC-group; n= 20), and a third apparently healthy control group (control-group; n= 10). RESULTS E-cad methylation showed non-significant differences between groups. P14 methylation was occurred only in HCC-group (45%). APC methylation was the highest in HCC group (70%). Methylation level was high in HCC group in comparison to both LC and control groups (P< 0.001). DNA methylation at a cutoff point > 2.9 ng/ml predicts HCC in LC-group with 90% sensitivity and 80% specificity and at level > 2.3 ng/ml had 95% sensitivity and 90% specificity in control-group. The pooled sensitivity, specificity, positive and negative predictive values and accuracy were 90%, 60%, 69.2, 85.7 and 75% respectively. CONCLUSION Aberrant DNA methylation of multiple genes is associated with disease progression in HCV related cirrhosis. Moreover, early detection of promotor methylation of these may sever as good biomarker for early detection and therapeutic targets in high risk patients.
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Affiliation(s)
- Mohamed A Mekky
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Rgaa H Salama
- Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud F Abdel-Aal
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Ghaliony
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Saad Zaky
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
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47
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Bharali D, Jebur HB, Baishya D, Kumar S, Sarma MP, Masroor M, Akhter J, Husain SA, Kar P. Expression Analysis of Serum microRNA-34a and microRNA-183 in Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2018; 19:2561-2568. [PMID: 30256056 PMCID: PMC6249442 DOI: 10.22034/apjcp.2018.19.9.2561] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/15/2018] [Indexed: 02/07/2023] Open
Abstract
Background/objective: HCC is a multistep process starting from chronic hepatitis that progress through cirrhosis to HCC. MicroRNA expression level was found to be deregulated in HCC. To find out whether the expression level of miR-34a and miR-183 was deregulated in HCC compared to controls without HCC. Methods: Real time quantitative PCR was done to find out the miRNA expression level in terms of Ct value followed by statistical analysis. Results: Over-expression of miR-183 and under-expression of miR-34a in HCC was detected. All changes in expression level of miR-34a and miR-183 were found to be due to HCC compared to controls without HCC. So both miR-34a and miR-183 were suitable to differentiate HCC from Cirrhosis and chronic hepatitis with an efficient diagnostic power of sensitivity, specificity and expression level. But they might not have any role in patients’ survival. Conclusion: miR- 34a and miR-183 might be considered as potential markers of HCC screening molecule in addition to other approved panel of marker. Our study warrants further expression level study.
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Affiliation(s)
- Dipu Bharali
- Department of Medicine, Maulana Azad Medical College, New Delhi, India.
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48
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Li Q, Deng C, Zhang T, Li X. Association of GSTP1 and P16 promoter methylation with the risk of HBV-related hepatocellular carcinoma: a meta-analysis. Onco Targets Ther 2018; 11:5789-5796. [PMID: 30254471 PMCID: PMC6140744 DOI: 10.2147/ott.s168444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Study on the relationship between glutathione-S-transferase Pi 1 (GSTP1) and P16 promoter region methylation and the risk of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) has produced inconsistent results. Objectives To assess the correlation between GSTP1 and P16 promoter methylation frequency and HBV-related HCC susceptibility. Methods All relevant studies were identified by searching PubMed, Embase, Web of Science, and China National Knowledge Infrastructure literature databases before December, 2017. The OR and the corresponding 95% CI were calculated to investigate the risk of GSTP1 and P16 promoter methylation rate and HBV-related HCC. Sensitivity analysis was performed and publication bias was estimated using the Begg’s and Egger’s test. Results Our meta-analysis identified the relationships of GSTP1 (six studies including 213 HBV-related HCC tumor tissues) and P16 (nine studies with 287 HBV-related HCC tumor tissue) promoter methylation with HCC risk. Compared with normal liver tissue and cirrhosis, the pooled ORs of GSTP1 promoter region methylation in HBV-related HCC cancer tissues were 6.05 (95% CI =1.20–30.52) and 5.21 (95% CI =2.19–12.41), respectively. Compared with paracancerous tissue, normal liver tissue, cirrhosis, and chronic hepatitis B as controls, the pooled ORs of P16 promoter region methylation in HBV-related HCC cancer tissues were 7.18 (95% CI =2.31–22.33), 24.89 (95% CI =3.38–183.03), 5.92 (95% CI =1.78–19.68), and 12.12 (95% CI =0.75–196.50). Conclusion In summary, our meta-analysis found strong associations between GSTP1 and P16 gene promoter methylation and an increased HBV-related HCC susceptibility. Moreover, GSTP1 and P16 methylation in promoter region could obviously increase the risk of HBV-related HCC in patients with cirrhosis, indicating that these would be promising biomarkers for early clinical diagnosis of HBV-related HCC.
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Affiliation(s)
- Qin Li
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Cunliang Deng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Ting Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China
| | - Xiang Li
- School of Pharmacy, The Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China,
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49
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Xie J, Zeng Q, Wang M, Ou X, Ma Y, Cheng A, Zhao XX, Liu M, Zhu D, Chen S, Jia R, Yang Q, Wu Y, Zhang S, Liu Y, Yu Y, Zhang L, Chen X. Transcriptomic Characterization of a Chicken Embryo Model Infected With Duck Hepatitis A Virus Type 1. Front Immunol 2018; 9:1845. [PMID: 30197639 PMCID: PMC6117380 DOI: 10.3389/fimmu.2018.01845] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 07/26/2018] [Indexed: 12/16/2022] Open
Abstract
Duck hepatitis A virus type 1 (DHAV-1) is one of the most common and lethal pathogens in young ducklings. Live-attenuated DHAV vaccine (CH60 strain) developed by passaging in chicken embryos provided effective immune protection for ducklings. However, the accurate mechanism for such adaption in chicken embryos is not fully revealed. Here, we utilize RNA-sequencing to perform global transcriptional analysis of DHAV-1-innoculated embryonated livers along with histopathological and ultrastructural analysis. This study revealed that infection with DHAV-1 strain CH60 is associated with enhanced type I and II interferon responses, activated innate immune responses, elevated levels of suppressor of cytokine signaling 1 and 3 (SOCS1 and SOCS3) accompanied with abnormalities in multiple metabolic pathways. Excessive inflammatory and innate immune responses induced by the CH60 strain are related to severe liver damage. Our study presents a comprehensive characterization of the transcriptome of chicken embryos infected with DHAV-CH60 and provides insight for in-depth exploration of viral adaption and virus-host interactions.
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Affiliation(s)
- Jinyan Xie
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
| | - Qiurui Zeng
- School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Xumin Ou
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
| | - Yunchao Ma
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Xin-Xin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
| | - Xiaoyue Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu City, China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, China
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Joung JG, Ha SY, Bae JS, Nam JY, Gwak GY, Lee HO, Son DS, Park CK, Park WY. Nonlinear tumor evolution from dysplastic nodules to hepatocellular carcinoma. Oncotarget 2018; 8:2076-2082. [PMID: 27409339 PMCID: PMC5356781 DOI: 10.18632/oncotarget.10502] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 05/17/2016] [Indexed: 12/21/2022] Open
Abstract
Dysplastic nodules are premalignant neoplastic nodules found in explanted livers with cirrhosis. Genetic signatures of premalignant dysplastic nodules (DNs) with concurrent hepatocellular carcinoma (HCC) may provide an insight in the molecular evolution of hepatocellular carcinogenesis. We analyzed four patients with multifocal nodular lesions and cirrhotic background by whole-exome sequencing (WES). The genomic profiles of somatic single nucleotide variations (SNV) and copy number variations (CNV) in DNs were compared to those of HCCs. The number and variant allele frequency of somatic SNVs of DNs and HCCs in each patient was identical along the progression of pathological grade. The somatic SNVs in DNs showed little conservation in HCC. Additionally, CNVs showed no conservation. Phylogenetic analysis based on SNVs and copy number profiles indicated a nonlinear segregation pattern, implying independent development of DNs and HCC in each patient. Thus, somatic mutations in DNs may be developed separately from other malignant nodules in the same liver, suggesting a nonlinear model for hepatocarcinogenesis from DNs to HCC.
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Affiliation(s)
- Je-Gun Joung
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Departments of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Seol Bae
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Yong Nam
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Departments of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hae-Ock Lee
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Departments of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dae-Soon Son
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Cheol-Keun Park
- Departments of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woong-Yang Park
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Departments of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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