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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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Zhao J, Hu Z, Zheng X, Lin Y, Liu X, Zhang J, Peng J, Gao H. Blood biomarkers of hepatocellular carcinoma: a critical review. Front Cell Dev Biol 2024; 12:1489836. [PMID: 39650722 PMCID: PMC11621223 DOI: 10.3389/fcell.2024.1489836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 12/11/2024] Open
Abstract
Hepatocellular Carcinoma (HCC) is a malignant tumor with high morbidity and mortality worldwide, which represents a serious threat to human life, health and quality of life. Blood-based detection is essential for HCC screening, early diagnosis, prognosis evaluation, and surveillance. Current non-invasive detection strategy including serum alpha-fetoprotein (AFP), ultrasound, computerized tomography, and magnetic resonance imaging. The limited specificity of an AFP and the dependence on operator experience and diagnostic personnel for ultrasound have constrained their utility in early HCC diagnosis. In recent years, with the development of various detection technologies, there has been an increasing focus on exploring blood-based detection markers for HCC. The types of markers include protein markers, DNA mutation, DNA epigenetic modification, mRNA, miRNA, and so on. However, numerous methodological and biological factors limit the clinical sensitivity and generalization performance of these new biomarkers. In this review, we describe the state-of-the-art technologies for cfDNA analysis, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve HCC diagnostics and patient care.
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Affiliation(s)
- Junsheng Zhao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zekai Hu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoping Zheng
- Hangzhou Tongchuang Medical Laboratory, Department of pathology, Hangzhou, China
| | - Yajie Lin
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiao Liu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Junjie Zhang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hainv Gao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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Lee JH, Hwang JA, Gu K, Shin J, Han S, Kim YK. Magnetic resonance elastography as a preoperative assessment for predicting intrahepatic recurrence in patients with hepatocellular carcinoma. Magn Reson Imaging 2024; 109:127-133. [PMID: 38513784 DOI: 10.1016/j.mri.2024.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/03/2024] [Accepted: 03/13/2024] [Indexed: 03/23/2024]
Abstract
PURPOSE Magnetic resonance elastography (MRE) is a noninvasive tool for diagnosing hepatic fibrosis with high accuracy. We investigated the preoperative clinical and imaging predictors of intrahepatic recurrence after curative resection of hepatocellular carcinoma (HCC), and evaluated MRE as a predictor of intrahepatic recurrence. METHODS We retrospectively evaluated 80 patients who underwent preoperative contrast-enhanced magnetic resonance imaging (MRI) with two-dimensional MRE and curative resection for treatment-naïve HCC between May 2019 and December 2021. Liver stiffness (LS) was measured on the elastograms, and the optimal cutoff of LS for predicting intrahepatic recurrence was obtained using receiver operating characteristic (ROC) analysis. An LS above this cutoff was defined as MRE-recurrence. Preoperative imaging features of the tumor were assessed on MRI, including features in the Liver Imaging Reporting and Data System and microvascular invasion (MVI). Recurrence-free survival (RFS) rates were estimated using the Kaplan-Meier method, and differences were compared using the log-rank test. Using a Cox proportional hazards model, we conducted a multivariable analysis to investigate the factors affecting recurrence-free survival. RESULTS During a median follow-up period of 32 months (range, 4-52 months), thirteen patients (16.3%) developed intrahepatic recurrence. ROC analysis determined an LS cutoff of ≥4.35 kPa to define MRE-recurrence. The 4-year RFS rate was significantly higher in patients without MRE-recurrence than in those with MRE-recurrence (93.4% vs. 48.9%; p = 0.001). In multivariable analysis, MRE-recurrence (Hazard ratio [HR], 5.9; 95% confidence interval [CI], 1.5-23.1) and MVI (HR, 3.4; 95% CI, 1.0-11.3) were independent predictors of intrahepatic recurrence. CONCLUSIONS Patients without MRE-recurrence had significantly higher RFS rates than those with MRE-recurrence. MRE-recurrence and MVI were independent predictors of intrahepatic recurrence in patients after curative resection for HCC.
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Affiliation(s)
- Jeong Hyun Lee
- Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeong Ah Hwang
- Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyowon Gu
- Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jaeseung Shin
- Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seungchul Han
- Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Kon Kim
- Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Huerne K, Jackson SS, Lall R, Palmour N, Berner AM, Dupras C, Joly Y. Studies in Cancer Epigenetics through a Sex and Gendered Lens: A Comprehensive Scoping Review. Cancers (Basel) 2023; 15:4207. [PMID: 37686484 PMCID: PMC10486657 DOI: 10.3390/cancers15174207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/18/2023] [Accepted: 08/20/2023] [Indexed: 09/10/2023] Open
Abstract
Background: Sex and gender are vitally important in the study of epigenetic mechanisms for various types of cancer. However, little has been done to assess the state of sex and gender-based analyses (SGBA) in this field. The aim was to undertake a critical evaluation of sex and gender representation, discussion, and data analysis within the cancer epigenetics field since 2010. Methods: A PRISMA-ScR scoping review was conducted with 111 peer-reviewed studies comprising of colorectal, gastric, head and neck, hepatocellular carcinoma, and lung cancers. Data extraction and a quality appraisal were performed by a team of epidemiologists and bioethicists. Results: Of the 111 included studies, only 17 studies (15.3%) explicitly stated sex and gender analysis to be their primary aim. A total of 103 studies (92.8%) provided a detailed analysis of sex/gender as a biological or social variable, while the remaining 8 studies (7.2%) only stratified results by sex/gender. Although sex and gender were a key facet in all the eligible studies, only 7 studies (6.3%) provided an explicit definition of the terms "sex" or "gender", while the remaining 104 studies (93.7%) used the words "sex" or "gender" without providing a definition. A total of 84 studies (75.7%) conflated the concepts of "sex" and "gender", while 44 studies (39.6%) were inconsistent with their usage of the "sex" and "gender" terms. Conclusions: Very few studies offered a robust analysis of sex/gender data according to SAGER guidelines. We call for clear and directed guidelines regarding the use of sex/gender as a variable in epigenetics research.
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Affiliation(s)
- Katherine Huerne
- Center of Genomics and Policy, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada
| | - Sarah S. Jackson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA
| | - Rina Lall
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC H3A 0G1, Canada
| | - Nicole Palmour
- Center of Genomics and Policy, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada
| | - Alison May Berner
- Department of Genomics & Computational Biology, Barts Cancer Institute, Queen Mary University of London, London E1 4NS, UK
| | - Charles Dupras
- Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Yann Joly
- Center of Genomics and Policy, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada
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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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Zhen J, Pan J, Zhou X, Yu Z, Jiang Y, Gong Y, Ding Y, Liu Y, Guo L. FARSB serves as a novel hypomethylated and immune cell infiltration related prognostic biomarker in hepatocellular carcinoma. Aging (Albany NY) 2023; 15:2937-2969. [PMID: 37074800 DOI: 10.18632/aging.204619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/09/2023] [Indexed: 04/20/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is a prevalent tumor with high morbidity, and an unfavourable prognosis. FARSB is an aminoacyl tRNA synthase, and plays a key role in protein synthesis in cells. Furthermore, previous reports have indicated that FARSB is overexpressed in gastric tumor tissues and is associated with a poor prognosis and tumorigenesis. However, the function of FARSB in HCC has not been studied. RESULTS The results showed that FARSB mRNA and protein levels were upregulated in HCC and were closely related to many clinicopathological characteristics. Besides, according to multivariate Cox analysis, high FARSB expression was linked with a shorter survival time in HCC and may be an independent prognostic factor. In addition, the FARSB promoter methylation level was negatively associated with the expression of FARSB. Furthermore, enrichment analysis showed that FARSB was related to the cell cycle. And TIMER analysis revealed that the FARSB expression was closely linked to tumor purity and immune cell infiltration. The TCGA and ICGC data analysis suggested that FARSB expression is greatly related to m6A modifier related genes. Potential FARSB-related ceRNA regulatory networks were also constructed. What's more, based on the FARSB-protein interaction network, molecular docking models of FARSB and RPLP1 were constructed. Finally, drug susceptibility testing revealed that FARSB was susceptible to 38 different drugs or small molecules. CONCLUSIONS FARSB can serve as a prognostic biomarker for HCC and provide clues about immune infiltration, and m6A modification.
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Affiliation(s)
- Jing Zhen
- Second Affiliated Hospital of Nanchang University, Nanchang, China
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Jingying Pan
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Xuanrui Zhou
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Zichuan Yu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yike Jiang
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yiyang Gong
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yongqi Ding
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yue Liu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Liangyun Guo
- Department of Ultrasonography, Second Affiliated Hospital of Nanchang University, Nanchang, 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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Hao Y, Yang Q, He Q, Hu H, Weng Z, Su Z, Chen S, Peng S, Kuang M, Chen Z, Xu L. Identification of DNA methylation signatures for hepatocellular carcinoma detection and microvascular invasion prediction. Eur J Med Res 2022; 27:276. [PMID: 36464701 PMCID: PMC9720918 DOI: 10.1186/s40001-022-00910-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/22/2022] [Indexed: 12/07/2022] Open
Abstract
BACKGROUND AND AIM Preoperative evaluation of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) is important for surgical strategy determination. We aimed to develop and establish a preoperative predictive model for MVI status based on DNA methylation markers. METHODS A total of 35 HCC tissues and the matched peritumoral normal liver tissues as well as 35 corresponding HCC patients' plasma samples and 24 healthy plasma samples were used for genome-wide methylation sequencing and subsequent methylation haplotype block (MHB) analysis. Predictive models were constructed based on selected MHB markers and 3-cross validation was used. RESULTS We grouped 35 HCC patients into 2 categories, including the MVI- group with 17 tissue and plasma samples, and MVI + group with 18 tissue and plasma samples. We identified a tissue DNA methylation signature with an AUC of 98.0% and a circulating free DNA (cfDNA) methylation signature with an AUC of 96.0% for HCC detection. Furthermore, we established a tissue DNA methylation signature for MVI status prediction, and achieved an AUC of 85.9%. Based on the MVI status predicted by the DNA methylation signature, the recurrence-free survival (RFS) and overall survival (OS) were significantly better in the predicted MVI- group than that in the predicted MVI + group. CONCLUSIONS In this study, we identified a cfDNA methylation signature for HCC detection and a tissue DNA methylation signature for MVI status prediction with high accuracy.
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Affiliation(s)
- Yijie Hao
- grid.412615.50000 0004 1803 6239Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China ,grid.412615.50000 0004 1803 6239Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China
| | - Qingxia Yang
- grid.412615.50000 0004 1803 6239Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China ,grid.412615.50000 0004 1803 6239Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong Province China
| | - Qiye He
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203 China
| | - Huanjing Hu
- grid.412615.50000 0004 1803 6239Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China
| | - Zongpeng Weng
- grid.12981.330000 0001 2360 039XDepartment of Biology and Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080 Guangdong Province China
| | - Zhixi Su
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203 China
| | - Shuling Chen
- grid.412615.50000 0004 1803 6239Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong Province China
| | - Sui Peng
- grid.412615.50000 0004 1803 6239Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China ,grid.412615.50000 0004 1803 6239Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong Province China
| | - Ming Kuang
- grid.412615.50000 0004 1803 6239Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China ,grid.412615.50000 0004 1803 6239Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China
| | - Zhihang Chen
- grid.412615.50000 0004 1803 6239Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China
| | - Lixia Xu
- grid.412615.50000 0004 1803 6239Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, 510080 Guangdong Province China ,grid.412615.50000 0004 1803 6239Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong Province China
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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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11
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Suzuki H, Iwamoto H, Yamamoto K, Tsukaguchi M, Nakamura T, Masuda A, Sakaue T, Tanaka T, Niizeki T, Okamura S, Shimose S, Shirono T, Noda Y, Kamachi N, Kuromatsu R, Hisaka T, Yano H, Koga H, Torimura T. DNA Methylation in Noncancerous Liver Tissues as Biomarker for Multicentric Occurrence of Hepatitis C Virus-Related Hepatocellular Carcinoma. GASTRO HEP ADVANCES 2022; 1:555-562. [PMID: 39132059 PMCID: PMC11307517 DOI: 10.1016/j.gastha.2022.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 02/16/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) progresses with a highly multicentric occurrence (MO) even after radical hepatectomy. Despite several efforts to clarify the pathogenesis of MO, the underlying molecular mechanism remains elusive. The aim of this study was to evaluate alterations in DNA methylation in noncancerous liver tissues in the MO of HCC. Methods A total of 203 patients with HCV-related HCC who underwent radical hepatectomy at our hospital between January 2008 and January 2012 were recruited. We defined a group of nonearly recurrence of HCC (NR) for ≥3 years after radical hepatectomy and a group of early recurrence of HCC (ER) with MO within 2 years after radical hepatectomy. Results Three patients each were selected in the NR and ER groups in the first set, and 13 patients in the NR group and 17 patients in the ER group were selected in the second set. Genome-wide DNA methylation profiles were obtained from noncancerous liver tissues using a Human Methylation 450 BeadChip, and the differences between the groups were analyzed for each set. After excluding single nucleotide polymorphism-associated methylation sites and low-call sites, 401,282 sites were assessed using a generalized linear model without any adjustments. Nine gene regions, APBB1P, CLSTN3, DLG5, IRX5, OAS1, SOX12, SNX19, TENM2, and TRIM54, exhibiting a significant difference (P < .001) in DNA methylation levels were identified in the common direction between the 2 analysis sets. Conclusion Alterations in DNA methylation of 9 genes in noncancerous liver tissues appear to be involved in MO after radical hepatectomy for HCV-related HCC.
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Affiliation(s)
- Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Ken Yamamoto
- Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan
| | - Mai Tsukaguchi
- Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toru Hisaka
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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12
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Tonon F, Cemazar M, Kamensek U, Zennaro C, Pozzato G, Caserta S, Ascione F, Grassi M, Guido S, Ferrari C, Cansolino L, Trotta F, Kuzmanov BG, Forte G, Martino F, Perrone F, Bomben R, Gattei V, Elvassore N, Murano E, Truong NH, Olson M, Farra R, Grassi G, Dapas B. 5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway. Cancers (Basel) 2022; 14:1630. [PMID: 35406401 PMCID: PMC8996928 DOI: 10.3390/cancers14071630] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/14/2022] [Accepted: 03/18/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND For hepatocellular carcinoma (HCC), effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to HCC development, demethylating drugs such as 5-azacytidine (5-Aza) have been proposed. As most 5-Aza mechanisms of action are unknown, we investigated its phenotypic/molecular effects. METHODS 5-Aza effects were examined in the human HCC cell lines JHH-6/HuH-7 and in the rat cell-line N1-S1. We also employed a xenograft mouse model (HuH-7), a zebrafish model (JHH-6), and an orthotopic syngeneic rat model (N1-S1) of HCC. RESULTS 5-Aza downregulated cell viability/growth/migration/adhesion by upregulating miR-139-5p, which in turn downregulated ROCK2/cyclin D1/E2F1 and increased p27kip1, resulting in G1/G0 cell accumulation. Moreover, a decrease in cyclin B1 and an increase in p27kip1 led to G2/M accumulation. Finally, we observed a decrease in MMP-2 levels, a stimulator of HCC cell migration. Aza effects were confirmed in the mouse model; in the zebrafish model, we also demonstrated the downregulation of tumor neo-angiogenesis, and in the orthotopic rat model, we observed impaired N1-S1 grafting in a healthy liver. CONCLUSION We demonstrate for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn impairs the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. Thus, we provide novel information about 5-Aza mechanisms of action and deepen the knowledge about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/p27kip1/MMP-2 in HCC.
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Affiliation(s)
- Federica Tonon
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (F.T.); (F.P.); (B.D.)
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (M.C.); (U.K.); (B.G.K.)
- Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia
| | - Urska Kamensek
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (M.C.); (U.K.); (B.G.K.)
| | - Cristina Zennaro
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume 447, I-34149 Trieste, Italy; (C.Z.); (G.P.)
| | - Gabriele Pozzato
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume 447, I-34149 Trieste, Italy; (C.Z.); (G.P.)
| | - Sergio Caserta
- Department of Chemical, Materials and Industrial Production Engineering, University of Naples “Federico II”, Piazzale V. Tecchio 80, I-80125 Naples, Italy; (S.C.); (F.A.); (S.G.)
- CEINGE Advanced Biotechnologies, via Gaetano Salvatore, 486, I-80145 Napoli, Italy
| | - Flora Ascione
- Department of Chemical, Materials and Industrial Production Engineering, University of Naples “Federico II”, Piazzale V. Tecchio 80, I-80125 Naples, Italy; (S.C.); (F.A.); (S.G.)
| | - Mario Grassi
- Department of Engineering and Architecture, University of Trieste, Via Valerio 6/A, I-34127 Trieste, Italy;
| | - Stefano Guido
- Department of Chemical, Materials and Industrial Production Engineering, University of Naples “Federico II”, Piazzale V. Tecchio 80, I-80125 Naples, Italy; (S.C.); (F.A.); (S.G.)
- CEINGE Advanced Biotechnologies, via Gaetano Salvatore, 486, I-80145 Napoli, Italy
| | - Cinzia Ferrari
- Department of Clinic-Surgical Sciences, Laboratory of Experimental Surgery and Animal Facility, University of Pavia, Via Ferrata 9, I-27100 Pavia, Italy; (C.F.); (L.C.)
| | - Laura Cansolino
- Department of Clinic-Surgical Sciences, Laboratory of Experimental Surgery and Animal Facility, University of Pavia, Via Ferrata 9, I-27100 Pavia, Italy; (C.F.); (L.C.)
| | - Francesco Trotta
- Department of General Surgery, Maggiore Hospital, Largo Donatori del Sangue 1, I-26900 Lodi, Italy;
| | - Biljana Grcar Kuzmanov
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (M.C.); (U.K.); (B.G.K.)
| | - Giancarlo Forte
- International Clinical Research Center (ICRC) of St Anne’s University Hospital, CZ-65691 Brno, Czech Republic; (G.F.); (F.M.)
| | - Fabiana Martino
- International Clinical Research Center (ICRC) of St Anne’s University Hospital, CZ-65691 Brno, Czech Republic; (G.F.); (F.M.)
| | - Francesca Perrone
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (F.T.); (F.P.); (B.D.)
- Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - Riccardo Bomben
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero a Cura a Carattere Scientifico IRCCS, 33081 Aviano, Italy; (R.B.); (V.G.)
| | - Valter Gattei
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero a Cura a Carattere Scientifico IRCCS, 33081 Aviano, Italy; (R.B.); (V.G.)
| | - Nicola Elvassore
- Industrial Engineering Department, University of Padova, Via Francesco Marzolo, 9, I-35131 Padova, Italy;
| | | | - Nhung Hai Truong
- Stem Cell Research and Application Laboratory, VNUHCM, University of Science, Ho Chi Minh City 72711, Vietnam;
| | - Michael Olson
- Department of Chemistry and Biology, X University, MaRS Discovery District, West Tower 661 University Avenue, Toronto, ON M5G 1M1, Canada;
| | - Rossella Farra
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (F.T.); (F.P.); (B.D.)
| | - Gabriele Grassi
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (F.T.); (F.P.); (B.D.)
| | - Barbara Dapas
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (F.T.); (F.P.); (B.D.)
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13
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Tahoon A, El-Khateeb D, Mosbeh A, Tantawy El Sayed I, Khalil A. Significance of promoter methylation of multiple tumor suppressor genes in hepatocellular carcinoma. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00237-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Abstract
Background
Methylation of the promoter at CpG islands is a mechanism of silencing tumor suppressor genes and therefore enhances cancer progression. The study aimed to examine promoter methylation frequencies of five tumor suppressor genes in hepatocellular carcinoma and their implication on the first-year outcome of surgical resection of the tumor. Fifty specimens of hepatocellular carcinoma and the adjacent non-tumorous liver tissue were collected from the surgically resected hepatic tumor. The status of promoter methylation of tumor suppressor genes RASSF1A, CHFR, MGMT, GSTP1, and hMLH1 was investigated using methylation-specific polymerase chain reaction.
Results
The frequency of promoter methylation of these tumor suppressors genes (TSG) genes in hepatocellular carcinoma was significantly higher than non-tumorous tissue all, P < 0.05, with a methylation rate of 80% in RASSF1A, 70% in CHFR, 46% in GSTP1, 56% in MGMT, and 10% in hMLH1. Methylation of RASSF1A, CHFR, and MGMT promoter genes was significantly associated with decreased first-year postoperative survival and increased recurrence of hepatocellular carcinoma, P < 0.05.
Conclusion
Methylated RASSF1A, CHRF, and MGMT promoters indicated poor prognosis among patients with hepatocellular carcinoma and may serve as potential prognostic indicators in patients with hepatocellular carcinoma.
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14
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Huang P, Xu M, Han H, Zhao X, Li MD, Yang Z. Integrative Analysis of Epigenome and Transcriptome Data Reveals Aberrantly Methylated Promoters and Enhancers in Hepatocellular Carcinoma. Front Oncol 2021; 11:769390. [PMID: 34858848 PMCID: PMC8631276 DOI: 10.3389/fonc.2021.769390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/14/2021] [Indexed: 12/15/2022] Open
Abstract
DNA methylation is a key transcription regulator, whose aberration was ubiquitous and important in most cancers including hepatocellular carcinoma (HCC). Whole-genome bisulfite sequencing (WGBS) was conducted for comparison of DNA methylation in tumor and adjacent tissues from 33 HCC patients, accompanying RNA-seq to determine differentially methylated region-associated, differentially expressed genes (DMR-DEGs), which were independently replicated in the TCGA-LIHC cohort and experimentally validated via 5-aza-2-deoxycytidine (5-azadC) demethylation. A total of 9,867,700 CpG sites showed significantly differential methylation in HCC. Integrations of mRNA-seq, histone ChIP-seq, and WGBS data identified 611 high-confidence DMR-DEGs. Enrichment analysis demonstrated activation of multiple molecular pathways related to cell cycle and DNA repair, accompanying repression of several critical metabolism pathways such as tyrosine and monocarboxylic acid metabolism. In TCGA-LIHC, we replicated about 53% of identified DMR-DEGs and highlighted the prognostic significance of combinations of methylation and expression of nine DMR-DEGs, which were more efficient prognostic biomarkers than considering either type of data alone. Finally, we validated 22/23 (95.7%) DMR-DEGs in 5-azadC-treated LO2 and/or HepG2 cells. In conclusion, integration of epigenome and transcriptome data depicted activation of multiple pivotal cell cycle-related pathways and repression of several metabolic pathways triggered by aberrant DNA methylation of promoters and enhancers in HCC.
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Affiliation(s)
- Peng Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengxiang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haijun Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyi Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming D Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China
| | - Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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15
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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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16
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Hagiwara S, Nishida N, Ueshima K, Minami Y, Komeda Y, Aoki T, Takita M, Morita M, Chishina H, Yoshida A, Ida H, Kudo M. Accumulation of Genetic and Epigenetic Alterations in the Background Liver and Emergence of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease. Cells 2021; 10:cells10113257. [PMID: 34831479 PMCID: PMC8619206 DOI: 10.3390/cells10113257] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/28/2022] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We analyzed 16 surgically resected HCC cases in which the background liver was pathologically diagnosed as NAFLD. Specimens with Brunt classification grade 3 or higher were assigned as the fibrotic progression group (n = 8), and those with grade 1 or lower were classified as the non-fibrosis progression group (n = 8). Comprehensive mutational and methylome analysis was performed in cancerous and noncancerous tissues. The target gene mutation analysis with deep sequencing revealed that CTNNB1 and TP53 mutation was observed in 37.5% and TERT promoter mutation was detected in 50% of cancerous samples. Furthermore, somatic mutations in non-cancerous samples were less frequent, but were observed regardless of the progression of fibrosis. Similarly, on cluster analysis of methylome data, status for methylation events involving non-cancerous liver was similar regardless of the progression of fibrosis. It was found that, even in cases of non-progressive fibrosis, accumulation of gene mutations and abnormal methylation within non-cancerous areas were observed. Patients with NAFLD require a rigorous liver cancer surveillance due to the high risk of HCC emergence based on the accumulation of genetic and epigenetic abnormalities, even when fibrosis is not advanced.
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17
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Bannaga AS, Alvarez R, Zhou L, Petchey M, Noufaily A, Hitchins MP, Arasaradnam RP. Role of methylated septin 9 as an adjunct diagnostic and prognostic biomarker in hepatocellular carcinoma. HPB (Oxford) 2021; 23:1595-1606. [PMID: 33931320 DOI: 10.1016/j.hpb.2021.03.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/24/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Methylated septin 9 (mSEPT9) has a role in hepatocarcinogenesis. We evaluated mSEPT9 performance in patients with hepatocellular carcinoma (HCC) and those at risk of HCC METHODS: Using Epi-proColon® V2.0 assay adapted for 1 mL plasma, we investigated mSEPT9 sensitivity, specificity, associations with influential covariates and relation to death. RESULTS Of 141 participants included, 136 had liver disease, 38 with HCC (mean-age 71 years) and 103 without HCC (mean-age 56.8 years), with further five without liver disease. 41 patients died (23 HCC) by the end of the study follow-up period. In HCC, mSEPT9 sensitivity and specificity were 89.47% (CI:75.20%-97.06%) and 81.55% (CI:72.70%-88.51%), whilst alpha fetoprotein (AFP) sensitivity and specificity were 50% (CI:33.38%-66.62%) and 97.09% (CI:91.72%-99.40%), respectively. Age-adjusted logistic regression showed mSEPT9 was associated with age, body mass index, HCC, liver cirrhosis, AFP, platelets, neutrophil-to-lymphocyte-ratio, albumin-bilirubin grade and fibrosis-4 index (p < 0.05). Odds for HCC patients to have positive mSEPT9 were 27.4 times more than those without HCC. Time-to-death was associated with mSEPT9 positivity (p < 0.05). Kaplan-Meier curves showed higher HCC survival with mSEPT9 compared to AFP. CONCLUSIONS The mSEPT9 offers potential diagnostic and prognostic biomarker for HCC. After adjusting for age, mSEPT9 remained associated with liver function, liver fibrosis and inflammatory surrogate markers.
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Affiliation(s)
- Ayman S Bannaga
- Department of Gastroenterology and Hepatology, University Hospital, Coventry UK; Warwick Medical School, University of Warwick, Coventry, UK.
| | - Rocio Alvarez
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles CA, USA
| | - Lisa Zhou
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles CA, USA
| | | | | | - Megan P Hitchins
- Department of Biomedical Sciences, Cedars-Sinai, Los Angeles CA, USA
| | - Ramesh P Arasaradnam
- Department of Gastroenterology and Hepatology, University Hospital, Coventry UK; Warwick Medical School, University of Warwick, Coventry, UK; Faculty of Health & Life Sciences, Coventry University, Coventry, UK; School of Biological Sciences, University of Leicester, Leicester, UK
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18
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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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19
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Prêle CM, Iosifidis T, McAnulty RJ, Pearce DR, Badrian B, Miles T, Jamieson SE, Ernst M, Thompson PJ, Laurent GJ, Knight DA, Mutsaers SE. Reduced SOCS1 Expression in Lung Fibroblasts from Patients with IPF Is Not Mediated by Promoter Methylation or Mir155. Biomedicines 2021; 9:biomedicines9050498. [PMID: 33946612 PMCID: PMC8147237 DOI: 10.3390/biomedicines9050498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/12/2021] [Accepted: 04/23/2021] [Indexed: 01/16/2023] Open
Abstract
The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5′-aza-2′-deoxycytidine’ treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by SOCS1 gene methylation or microRNA155 in these cells. In conclusion, we confirmed that IPF fibroblasts had lower levels of SOCS1 mRNA compared with control fibroblasts, but we were unable to determine the mechanism. Furthermore, although SOCS1 may be important in the fibrotic process, we were unable to find a significant role for SOCS1 in regulating fibroblast function.
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Affiliation(s)
- Cecilia M. Prêle
- Institute for Respiratory Health, Nedland, WA 6009, Australia; (C.M.P.); (T.I.); (B.B.); (T.M.); (P.J.T.); (G.J.L.)
- Centre for Respiratory Health and Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, University of Western Australia, Nedland, WA 6009, Australia
| | - Thomas Iosifidis
- Institute for Respiratory Health, Nedland, WA 6009, Australia; (C.M.P.); (T.I.); (B.B.); (T.M.); (P.J.T.); (G.J.L.)
| | - Robin J. McAnulty
- Centre for Inflammation and Tissue Repair, Rayne Institute, Department of Medicine, University College London, London WC1E 6JJ, UK; (R.J.M.); (D.R.P.)
| | - David R. Pearce
- Centre for Inflammation and Tissue Repair, Rayne Institute, Department of Medicine, University College London, London WC1E 6JJ, UK; (R.J.M.); (D.R.P.)
| | - Bahareh Badrian
- Institute for Respiratory Health, Nedland, WA 6009, Australia; (C.M.P.); (T.I.); (B.B.); (T.M.); (P.J.T.); (G.J.L.)
| | - Tylah Miles
- Institute for Respiratory Health, Nedland, WA 6009, Australia; (C.M.P.); (T.I.); (B.B.); (T.M.); (P.J.T.); (G.J.L.)
| | - Sarra E. Jamieson
- Telethon Kids Institute and Centre for Child Health Research, University of Western Australia, Nedlands, WA 6009, Australia;
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
| | - Philip J. Thompson
- Institute for Respiratory Health, Nedland, WA 6009, Australia; (C.M.P.); (T.I.); (B.B.); (T.M.); (P.J.T.); (G.J.L.)
| | - Geoffrey J. Laurent
- Institute for Respiratory Health, Nedland, WA 6009, Australia; (C.M.P.); (T.I.); (B.B.); (T.M.); (P.J.T.); (G.J.L.)
- Centre for Respiratory Health and Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, University of Western Australia, Nedland, WA 6009, Australia
| | - Darryl A. Knight
- Faculty of Medicine, University of British Columbia (UBC), Vancouver, BC V6Z 1Y5, Canada;
| | - Steven E. Mutsaers
- Institute for Respiratory Health, Nedland, WA 6009, Australia; (C.M.P.); (T.I.); (B.B.); (T.M.); (P.J.T.); (G.J.L.)
- Centre for Respiratory Health and Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, University of Western Australia, Nedland, WA 6009, Australia
- Correspondence: ; Tel.: +61-(0)8-6151-0891; Fax: +61-(0)8-6151-1027
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20
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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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21
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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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22
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Fan X, Li Y, Yi X, Chen G, Jin S, Dai Y, Cui B, Dai B, Lin H, Zhou D. Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients. Neoplasia 2020; 22:630-643. [PMID: 33059309 PMCID: PMC7566847 DOI: 10.1016/j.neo.2020.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022] Open
Abstract
Aberrant methylation is a hallmark of hepatocellular carcinoma and plays an important role in tumor initiation and progression. However, the epigenome-wide methylation patterns of portal vein tumor thrombosis (PVTTs) have not been fully explored. Here, we performed epigenome-wide DNA methylation of adjacent normal tissues (ANTs), paired tumor tissues and paired PVTTs using an Infinium HumanMethylation450 array (n = 11) and conducted the Sequenom EpiTYPER assays to confirm the aberrantly methylated genes. MTS and apoptosis assay were used to assess the synergistic effect of two drugs on the HCC cell lines. We found the mean global methylation levels of HCC tissues and PVTTs were significantly lower than ANTs (P < 0.01). A total of 864 differentially methylated CpG sites annotated in 532 genes were identified between HCC tissues and paired PVTTs (|mean methylation difference|>10%, P < 0.005). The pathway analysis based on hypermethylated genes in PVTT tissues was interestingly enriched in regulation of actin cytoskeleton pathway (P = 4.48E−5). We found 23 genes whose methylation levels were gradually alternated in HCC tissues and PVTTs. Aberrant methylation status of TNFRSF10A, ZC3H3 and SLC9A3R2 were confirmed in a validation cohort (n = 48). The functional experiments demonstrated the combination of decitabine (DAC) and tumor necrosis factor-related apoptosis-inducing ligand (rh-TRAIL) could synergistically suppress the proliferation and induce apoptosis in SK-Hep-1 and Huh7 cell lines. Together, our findings indicated that DNA methylation plays an important role in the PVTT formation through regulating the metastasis-related pathways. The combination of DAC and rh-TRAIL might be a promising treatment strategy for HCC.
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Affiliation(s)
- Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xin Yi
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Guoqiao Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yili Dai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bin Cui
- College of Life Science and Technology, Nanyang Normal University, Nanyang, China
| | - Binghua Dai
- Department of Special Treatment Ⅰ and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Daizhan Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Jiao Tong University, Shanghai, China.
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23
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Nishida N. Long-term prognosis and management of hepatocellular carcinoma after curative treatment. Clin Mol Hepatol 2020; 26:480-483. [PMID: 32951413 PMCID: PMC7641545 DOI: 10.3350/cmh.2020.0208] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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24
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Nishida N, Kudo M. Immune Phenotype and Immune Checkpoint Inhibitors for the Treatment of Human Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:E1274. [PMID: 32443599 PMCID: PMC7281618 DOI: 10.3390/cancers12051274] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/06/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
Immunotherapies are promising approaches for treating hepatocellular carcinomas (HCCs) refractory to conventional therapies. However, a recent clinical trial of immune checkpoint inhibitors (ICIs) revealed that anti-tumor responses to ICIs are not satisfactory in HCC cases. Therefore, it is critical to identify molecular markers to predict outcome and develop novel combination therapies that enhance the efficacy of ICIs. Recently, several attempts have been made to classify HCC based on genome, epigenome, and transcriptome analyses. These molecular classifications are characterized by unique clinical and histological features of HCC, as well immune phenotype. For example, HCCs exhibiting gene expression patterns with proliferation signals and stem cell markers are associated with the enrichment of immune infiltrates in tumors, suggesting immune-proficient characteristics for this type of HCC. However, the presence of activating mutations in β-catenin represents a lack of immune infiltrates and refractoriness to ICIs. Although the precise mechanism that links the immunological phenotype with molecular features remains controversial, it is conceivable that alterations of oncogenic cellular signaling in cancer may lead to the expression of immune-regulatory molecules and result in the acquisition of specific immunological microenvironments for each case of HCC. Therefore, these molecular and immune characteristics should be considered for the management of HCC using immunotherapy.
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Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine; 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan;
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25
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Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment. J Hepatocell Carcinoma 2020; 7:45-76. [PMID: 32346535 PMCID: PMC7167284 DOI: 10.2147/jhc.s221187] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
- Department of Medicine, Division of Gastroenterology, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Kyle E Widmer
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
| | - Leela Nayak
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
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26
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Chen L, Huang W, Wang L, Zhang Z, Zhang F, Zheng S, Kong D. The effects of epigenetic modification on the occurrence and progression of liver diseases and the involved mechanism. Expert Rev Gastroenterol Hepatol 2020; 14:259-270. [PMID: 32124651 DOI: 10.1080/17474124.2020.1736042] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Epigenetic modification is a type of gene expression and regulation that does not involve changes in DNA sequences. An increasing number of studies have proven that epigenetic modifications play an important role in the occurrence and progression of liver diseases through the gene regulation and protein expressions of hepatocellular lipid metabolism, inflammatory reaction, cell proliferation, and activation, etc.Areas covered: In this study, we elaborated and analyzed the underlying functional mechanism of epigenetic modification in alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), liver fibrosis (LF), viral hepatitis, hepatocellular carcinoma (HCC), and research progress of recent years.Expert opinion: The further understanding of epigenetic mechanisms that can regulate gene expression and cell phenotype leads to new insights in epigenetic control of chronic liver disease. Currently, hepatologists are exploring the role of DNA methylation, histone/chromatin modification, and non-coding RNA in specific liver pathology. These findings have led to advances in direct epigenetic biomarker testing of patient tissue or body fluid specimens, as well as quantitative analysis. Based on these findings, drug validation of some targets involved in the epigenetic mechanism of liver disease is gradually being carried out clinically.
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Affiliation(s)
- Liping Chen
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weifang Huang
- Department of Pharmacology, School of Integral Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ling Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Desong Kong
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Ding J, Xu K, Sun S, Qian C, Yin S, Xie H, Zhou L, Zheng S, Zhang W. SOCS1 blocks G1-S transition in hepatocellular carcinoma by reducing the stability of the CyclinD1/CDK4 complex in the nucleus. Aging (Albany NY) 2020; 12:3962-3975. [PMID: 32096766 PMCID: PMC7066915 DOI: 10.18632/aging.102865] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/04/2020] [Indexed: 12/24/2022]
Abstract
Inhibitors of the CDK family of proteins have been approved for the treatment of a variety of tumours; however, the development of new drugs administered in combination with CDK inhibitors is expected to improve the therapeutic effect. We identified the function of suppressor of cytokine signalling 1 (SOCS1) in hepatocellular carcinoma (HCC) cell models and the xenograft mouse model. When SOCS1 expression was artificially upregulated, HCC cell lines were arrested at the G1-S transition in the cell cycle. Interestingly, during this process, total CyclinD1 protein increased, but the effective proportion decreased. We found that the deficiency of CyclinD1 in the nucleus is probably due to the decrease in the stability of nuclear CyclinD1 caused by the ubiquitin-based degradation of P21, thus inhibiting the progression of the cell cycle to S phase. After P21 expression was increased, the levels of the component that inactivates CyclinD1 decreased as expected. It showed that P21 has a partial promoting effect on cancer. SOCS1 is a good indicator of prognosis, tumour size and long-term survival after resection. SOCS1 is expected to become a drug target in combined with CDK family inhibitors.
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Affiliation(s)
- Jun Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Kangdi Xu
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.,Ningbo Medical Center LIHUILI Hospital, Ningbo, Zhejiang Province, China
| | - Suwan Sun
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China.,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang Province, China
| | - Chao Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Shengyong Yin
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Lin Zhou
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China
| | - Wei Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
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28
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Paluvai H, Di Giorgio E, Brancolini C. The Histone Code of Senescence. Cells 2020; 9:cells9020466. [PMID: 32085582 PMCID: PMC7072776 DOI: 10.3390/cells9020466] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 12/12/2022] Open
Abstract
Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.
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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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30
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Cai C, Xie X, Zhou J, Fang X, Wang F, Wang M. Identification of TAF1, SAT1, and ARHGEF9 as DNA methylation biomarkers for hepatocellular carcinoma. J Cell Physiol 2020; 235:611-618. [PMID: 31283007 DOI: 10.1002/jcp.28999] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 06/04/2019] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. More than 90% of primary HCC is HCC. Hepatitis C virus (HCV) infection and alcohol consumption have been widely accepted as two major risk factors for developing HCC. Herein, we aimed to identify DNA methylation genes related to both HCV infection and alcohol consumption. In this study, we identified methylation genes that were associated with the risk of HCV infection and alcohol consumption, respectively, by a large-scale bioinformatic analysis. Through PPI network analysis, we revealed the associations between the two types of genes and found six hub genes-TAF1, SAT1, Phospholipase C-beta 2, FGD1, ARHGAP4, and ARHGEF9-that may be associated with both HCV infection and alcohol consumption. Gene Ontology enrichment analysis was used to analyze the function which these genes in the network enriched. Among them, TAF1, SAT1, and ARHGEF9 were methylated genes that have been found to be related to tumor progression in HCC patients. Through independent data sets, we verified the methylation pattern of these six genes in HCC samples that had both HCV infection and alcohol consumption risks. Furthermore, we found that three of the six methylated genes were also associated with the prognosis of HCC patients. To summarize, we identified six hub genes that were associated with both HCV infection and alcohol consumption in the progress of HCC. The six methylation genes that might play an important role in both HCV infection and alcohol consumption would be potential therapy targets for HCC.
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Affiliation(s)
- Chudong Cai
- Department of General Surgery, Shantou Central Hospital and The Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - Xiaojun Xie
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Junyi Zhou
- Department of General Surgery, Shantou Central Hospital and The Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - Xi Fang
- Department of General Surgery, Shantou Central Hospital and The Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - Fang Wang
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Wang
- Department of Rehabilitation, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
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31
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Xiong Z, Alves CS, Wang J, Li A, Liu J, Shen M, Rodrigues J, Tomás H, Shi X. Zwitterion-functionalized dendrimer-entrapped gold nanoparticles for serum-enhanced gene delivery to inhibit cancer cell metastasis. Acta Biomater 2019. [DOI: https://doi.org/10.1016/j.actbio.2019.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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32
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Xiong Z, Alves CS, Wang J, Li A, Liu J, Shen M, Rodrigues J, Tomás H, Shi X. Zwitterion-functionalized dendrimer-entrapped gold nanoparticles for serum-enhanced gene delivery to inhibit cancer cell metastasis. Acta Biomater 2019; 99:320-329. [PMID: 31513912 DOI: 10.1016/j.actbio.2019.09.005] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/05/2019] [Accepted: 09/05/2019] [Indexed: 02/05/2023]
Abstract
We demonstrate a novel serum-enhanced gene delivery approach using zwitterion-functionalized dendrimer-entrapped gold nanoparticles (Au DENPs) as a non-viral vector for inhibition of cancer cell metastasis in vitro. Poly(amidoamine) dendrimers of generation 5 decorated with zwitterion carboxybetaine acrylamide (CBAA) and lysosome-targeting agent morpholine (Mor) were utilized to entrap gold NPs. We show that both Mor-modified and Mor-free Au DENPs are cytocompatible and can effectively deliver plasmid DNA encoding different reporter genes to cancer cells in medium with or without serum. Strikingly, due to the antifouling property exerted by the attached zwitterion CBAA, the gene delivery efficiency of Mor-modified Au DENPs and the Mor-free Au DENPs in the serum-containing medium are 1.4 and 1.7 times higher than the corresponding vector in serum-free medium, respectively. In addition, the Mor-free vector has a better gene expression efficiency than the Mor-modified one although the Mor modification enables the polyplexes to have enhanced cancer cell uptake. Wound healing and hypermethylated in cancer 1 (HIC1) protein expression assay data reveal that the expression of HIC1 gene in cancer cells enables effective inhibition of cell migration. Our findings suggest that the created zwitterion-functionalized Au DENPs may be employed as a powerful vector for serum-enhanced gene therapy of different diseases. STATEMENT OF SIGNIFICANCE: One major challenge in the non-viral gene delivery system is that the strong interaction between serum protein and the positively charged vector/gene polyplexes neutralize the positive charge of the polyplexes and form possible protein corona, thereby significantly reducing their cellular uptake efficiency and subsequent gene transfection outcome. Here we demonstrate the conceptual advances in the serum-enhanced gene delivery using zwitterionic modification of polycationic poly(amidoamine) (PAMAM) dendrimer-entrapped gold nanoparticles (Au DENPs). We demonstrate that partial zwitterionic modification of Au DENPs is able to confer them with antifouling property to resist serum protein adsorption. Hence the vector/DNA polyplexes are able to maintain their positive potentials and small hydrodynamic size in the serum environment, where serum solely play the role as a nutrition factor for enhanced gene delivery. We demonstrate that partial modification of zwitterion carboxybetaine acrylamide (CBAA) and morpholine (Mor) onto the surface Au DENPs renders the vector with both antifouling property and lysosome targeting ability, respectively. The generated functional Au DENPs can compact pDNA to form polyplexes that enable serum-enhanced gene expression. In particular, once complexed with hypermethylated in cancer 1 (HIC1) gene, the polyplexes can significantly inhibit cancer cell migration and metastasis.
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Affiliation(s)
- Zhijuan Xiong
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China
| | - Carla S Alves
- CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal
| | - Jianhua Wang
- Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China; School of Medicine, Anhui University of Science & Technology, Huainan 232001, People's Republic of China
| | - Aijun Li
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China
| | - Jinyuan Liu
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China
| | - Mingwu Shen
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China
| | - João Rodrigues
- CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal
| | - Helena Tomás
- CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China; CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.
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Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Kato T, Nakagama H, Ochiya T. MEG3-derived miR-493-5p overcomes the oncogenic feature of IGF2-miR-483 loss of imprinting in hepatic cancer cells. Cell Death Dis 2019; 10:553. [PMID: 31320614 PMCID: PMC6639415 DOI: 10.1038/s41419-019-1788-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/10/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023]
Abstract
Numerous studies have described the critical role played by microRNAs (miRNAs) in cancer progression and the potential of these small non-coding RNAs for diagnostic or therapeutic applications. However, the mechanisms responsible for the altered expression of miRNAs in malignant cells remain poorly understood. Herein, via epigenetic unmasking, we identified a group of miRNAs located in the imprinted delta like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3 (MEG3) locus that were repressed in hepatic tumor cells. Notably, miR-493-5p epigenetic silencing was correlated with hypermethylation of the MEG3 differentially regulated region (DMR) in liver cancer cell lines and tumor tissues from patients. Experimental rescue of miR-493-5p promoted an anti-cancer response by hindering hepatocellular carcinoma (HCC) cell growth in vitro and tumor progression in vivo. We found that miR-493-5p mediated part of its tumor-suppressor activity by abrogating overexpression of insulin-like growth factor 2 (IGF2) and the IGF2-derived intronic oncomir miR-483-3p in HCC cells characterized by IGF2 loss of imprinting (LOI). In summary, this study describes an unknown miRNA-dependent regulatory mechanism between two distinct imprinted loci and a possible therapeutic window for liver cancer patients exhibiting IGF2-miR-483 LOI and amplification.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Survival/genetics
- DNA Methylation
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic/genetics
- Genes, Tumor Suppressor
- Genomic Imprinting/genetics
- Humans
- Insulin-Like Growth Factor II/genetics
- Insulin-Like Growth Factor II/metabolism
- Introns
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Mice
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Transplantation, Heterologous
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Affiliation(s)
- Luc Gailhouste
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
- Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
| | - Lee Chuen Liew
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
- Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ken Yasukawa
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
- Department of Integrative Bioscience and Biomedical Engineering, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Izuho Hatada
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Kato
- Department of Integrative Bioscience and Biomedical Engineering, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Hitoshi Nakagama
- Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- National Cancer Center, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1 Shinjuku-ku, Tokyo, 160-0023, Japan.
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Li GX, Ding ZY, Wang YW, Liu TT, Chen WX, Wu JJ, Xu WQ, Zhu P, Zhang BX. Integrative analysis of DNA methylation and gene expression identify a six epigenetic driver signature for predicting prognosis in hepatocellular carcinoma. J Cell Physiol 2019; 234:11942-11950. [PMID: 30536816 DOI: 10.1002/jcp.27882] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 11/12/2018] [Indexed: 12/12/2022]
Abstract
DNA methylation is a crucial regulator of gene transcription in the etiology and pathogenesis of hepatocellular carcinoma (HCC). Thus, it is reasonable to identify DNA methylation-related prognostic markers. Currently, we aimed to make an integrative epigenetic analysis of HCC to identify the effectiveness of epigenetic drivers in predicting prognosis for HCC patients. By the software pipeline TCGA-Assembler 2, RNA-seq, and methylation data were downloaded and processed from The Cancer Genome Atlas. A bioconductor package MethylMix was utilized to incorporate gene expression and methylation data on all 363 samples and identify 589 epigenetic drivers with transcriptionally predictive. By univariate survival analysis, 72 epigenetic drivers correlated with overall survival (OS) were selected for further analysis in our training cohort. By the robust likelihood-based survival model, six epi-drivers (doublecortin domain containing 2, flavin containing monooxygenase 3, G protein-coupled receptor 171, Lck interacting transmembrane adaptor 1, S100 calcium binding protein P, small nucleolar RNA host gene 6) serving as prognostic markers was identified and then a DNA methylation signature for HCC (MSH) predicting OS was identified to stratify patients into low-risk and high-risk groups in the training cohort (p < 0.001). The capability of MSH was also assessed in the validation cohort (p = 0.002). Furthermore, a receiver operating characteristic curve confirmed MSH as an effective prognostic model for predicting OS in HCC patients in training area under curve (AUC = 0.802) and validation (AUC = 0.691) cohorts. Finally, a nomogram comprising MSH and pathologic stage was generated to predict OS in the training cohort, and it also operated effectively in the validation cohort (concordance index: 0.674). In conclusion, MSH, a six epi-drivers based signature, is a potential model to predict prognosis for HCC patients.
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Affiliation(s)
- Gan-Xun Li
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ze-Yang Ding
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu-Wei Wang
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tong-Tong Liu
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei-Xun Chen
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing-Jing Wu
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei-Qi Xu
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zhu
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bi-Xiang Zhang
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Yokomichi N, Nishida N, Umeda Y, Taniguchi F, Yasui K, Toshima T, Mori Y, Nyuya A, Tanaka T, Yamada T, Yagi T, Fujiwara T, Yamaguchi Y, Goel A, Kudo M, Nagasaka T. Heterogeneity of Epigenetic and Epithelial Mesenchymal Transition Marks in Hepatocellular Carcinoma with Keratin 19 Proficiency. Liver Cancer 2019; 8:239-254. [PMID: 31602368 PMCID: PMC6738240 DOI: 10.1159/000490806] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 06/09/2018] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE Keratin 19 (K19) expression is a potential predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). To clarify the feature of K19-proficient HCC, we traced epigenetic footprints in cultured cells and clinical materials. PATIENTS AND METHODS In vitro, KRT19 promoter methylation was analyzed and 5-aza-2'-deoxycytidine with trichostatin A (TSA) treatment was performed. Among 564 surgically resected HCCs, the clinicopathological relevance of K19-proficent HCCs was performed in comparison with hepatocytic (HepPar-1 and arginase-1), epithelial-mesenchymal transition (E-cadherin and vimentin), biliary differentiation-associated (K7 and NOTCH-1) markers, and epigenetic markers (KRT19 promoter/long interspersed nucleotide element-1 [LINE-1] methylation status). RESULTS KRT19 promoter methylation was clearly associated with K19 deficiency and 5-aza-2'-deoxycytidine with TSA treatment-stimulated K19 re-expression, implicating DNA methylation as a potential epigenetic process for K19 expression. After excluding HCCs with recurrence, TNM stage as IIIB or greater, preoperative therapy, transplantation, and combined hepatocellular cholangiocarcinoma, we assessed 125 of 564 HCC cases. In this cohort, K19 expression was found in 29 HCCs (23.2%) and corresponded with poor survival following surgery (p = 0.025) and extrahepatic recurrence-free survival (p = 0.017). Compared with K19-deficient HCCs, lower KRT19 promoter methylation level was observed in K19-proficient HCCs (p < 0.0001). Conversely, HCC with genome-wide LINE-1 hypermethylation was frequently observed in K19-proficient HCCs (p = 0.0079). Additionally, K19 proficiency was associated with K7 proficiency (p = 0.043), and reduced E-cadherin and HepPar-1 expression (p = 0.043 and p < 0.0001, respectively). CONCLUSIONS K19-proficient HCC exhibited poor prognosis owing to extrahepatic recurrence, with molecular signatures differing from those in conventional cancer stem cells, providing novel insights of the heterogeneity underlying tumor development.
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Affiliation(s)
- Naosuke Yokomichi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yuzo Umeda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Fumitaka Taniguchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuya Yasui
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Toshiaki Toshima
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshiko Mori
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Akihiro Nyuya
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan,Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Takeshi Yamada
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Takahito Yagi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Ajay Goel
- Center for Gastrointestinal Cancer Research, Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takeshi Nagasaka
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan,Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Japan,*Takeshi Nagasaka, MD, PhD, Department of Clinical Oncology, Kawasaki Medical School, Kurashiki City, Okayama 701-0192 (Japan), E-Mail
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LINE-1 hypomethylation in human hepatocellular carcinomas correlates with shorter overall survival and CIMP phenotype. PLoS One 2019; 14:e0216374. [PMID: 31059558 PMCID: PMC6502450 DOI: 10.1371/journal.pone.0216374] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 04/18/2019] [Indexed: 02/08/2023] Open
Abstract
Reactivation of interspersed repetitive sequences due to loss of methylation is associated with genomic instability, one of the hallmarks of cancer cells. LINE-1 hypomethylation is a surrogate marker for global methylation loss and is potentially a new diagnostic and prognostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinicopathological parameters and the CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined, particularly in Caucasians who show quite low rates of HCV/HBV infection and a higher incidence of liver steatosis. Therefore, quantitative DNA methylation analysis of LINE-1, RASSF1A, and CCND2 using pyrosequencing was performed in human hepatocellular carcinomas (HCC, n = 40), hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5), and corresponding peritumoral liver tissues as well as healthy liver tissues (n = 5) from Caucasian patients. Methylation results were correlated with histopathological findings and clinical data. We found loss of LINE-1 DNA methylation only in HCC. It correlated significantly with poor survival (log rank test, p = 0.007). An inverse correlation was found for LINE-1 and RASSF1A DNA methylation levels (r2 = -0.47, p = 0.002). LINE-1 hypomethylation correlated with concurrent RASSF1/CCND2 hypermethylation (Fisher’s exact test, p = 0.02). Both LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation were not found in benign hepatocellular tumors (HCA and FNH). Our results show that LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation are epigenetic aberrations specific for the process of malignant liver transformation. In addition, LINE-1 hypomethylation might serve as a future predictive biomarker to identify HCC patients with unfavorable overall survival.
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Gurioli G, Martignano F, Salvi S, Costantini M, Gunelli R, Casadio V. GSTP1 methylation in cancer: a liquid biopsy biomarker? Clin Chem Lab Med 2019; 56:702-717. [PMID: 29305565 DOI: 10.1515/cclm-2017-0703] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 10/31/2017] [Indexed: 12/14/2022]
Abstract
The coding region of GSTP1 gene is preceded by a large CpG-rich region that is frequently affected by methylation. In many cancer types, GSTP1 is affected by hypermethylation and, as a consequence, it has a low expression. The aim of this review is to give an overview on GSTP1 methylation studies with a special focus on liquid biopsy, thus to summarize methods, results, sample types, different diseases, to have a complete information regarding this promising epigenetic biomarker. We used all the most valuable scientific search engines (PubMed, Medline, Scopus and Web of Science) searching the following keywords: GSTP1, methylation, cancer, urine, serum, plasma and blood. GSTP1 is a largely investigated tissue biomarker in several malignancies such as prostate, breast, lung and hepatocellular carcinoma with good performances especially for diagnostic purposes. As a liquid biopsy biomarker, it has been mainly investigated in prostate cancer (PCa) where it showed a high specificity but a low sensitivity; thus, it is recommended in combination with other biomarkers. Despite the large number of published papers and the promising results, GSTP1 has not yet entered the clinical practice even for PCa diagnosis. For this reason, further large and prospective studies are needed to validate this assay.
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Affiliation(s)
- Giorgia Gurioli
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Filippo Martignano
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.,Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Samanta Salvi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Matteo Costantini
- Pathology Unit, Department of Medical Oncology, Morgagni Pierantoni Hospital, Forlì, Italy
| | - Roberta Gunelli
- Department of Urology, Morgagni Pierantoni Hospital, Forli, Italy
| | - Valentina Casadio
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Dynamic expression of ZNF382 and its tumor-suppressor role in hepatitis B virus-related hepatocellular carcinogenesis. Oncogene 2019; 38:4804-4819. [PMID: 30804458 DOI: 10.1038/s41388-019-0759-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 12/24/2018] [Accepted: 02/10/2019] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC). Zinc-finger protein 382 (ZNF382), which belongs to zinc-finger protein family, has been documented to be downregulated in certain types of cancer. However, its role in HCC remains largely unknown. In this study, we demonstrated that ZNF382 expression was significantly elevated in HBV-infected liver cirrhosis tissues relative to HBV-negative normal liver tissues at protein levels, but not at mRNA levels, and was positively correlated with the levels of HBV DNA and hepatitis B virus X protein (HBx). Further studies revealed that ZNF382 was a target of miR-6867, and HBx promoted the translation of ZNF382 during HBV chronic infection through Erk-mediated miR-6867 inhibition. In addition, our data showed that ZNF382 was frequently downregulated by promoter methylation in HBV-related HCCs relative to HBV-infected liver cirrhosis tissues, and decreased expression of ZNF382 was strongly correlated with poor survival in early-stage HCC patients. Functional studies demonstrated that ZNF382 was a potent tumor suppressor in HCC cells through inhibiting cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice, and inducing cell apoptosis. Mechanistically, ZNF382 exerted its tumor-suppressor functions in HCC through transcriptionally repressing its downstream targets such as Fos proto-oncogene (FOS), Jun proto-oncogene (JUN), disheveled segment polarity protein 2 (DVL2), and frizzled class receptor 1 (FZD1), thereby impairing the activities of activating protein 1 (AP-1) and Wnt/β-catenin pathways and activating p53 signaling. Altogether, our data show that ZNF382 acts as a tumor suppressor, and is co-regulated by HBx and epigenetic mechanism in HBV-related hepatocellular carcinogenesis.
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Chen Z, Zuo X, Pu L, Zhang Y, Han G, Zhang L, Wu J, Wang X. circLARP4 induces cellular senescence through regulating miR-761/RUNX3/p53/p21 signaling in hepatocellular carcinoma. Cancer Sci 2019; 110:568-581. [PMID: 30520539 PMCID: PMC6361555 DOI: 10.1111/cas.13901] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/22/2018] [Accepted: 11/25/2018] [Indexed: 12/31/2022] Open
Abstract
Circular RNAs (circRNAs), a novel class of non-coding RNAs, have emerged as indispensable modulators in human malignancies. Aberrant cellular senescence is a phenotype observed in various cancers. The association of circRNAs with cellular senescence in tumors is yet to determined. Here, we investigated the role of circLARP4 in cellular senescence and cell proliferation in hepatocellular carcinoma (HCC). Downregulated circLARP4 level was observed in HCC tissues and cell lines. Low expression level of circLARP4 independently predicted poor survival outcome. Gain-of-function and loss-of-function assays demonstrated that circLARP4 suppressed HCC cell proliferation, mediated cell cycle arrest and induced senescence in vitro. Levels of p53 and p21, 2 key regulatory molecules in cellular senescence, were increased in circLARP4-overexpressed HCC cells and decreased in circLARP4-silenced HCC cells. In vivo experiments further confirmed the tumor-suppressing activity of circLARP4. Further mechanistic studies showed that circLARP4 dampened HCC progression by sponging miR-761, thereby promoting the expression level of RUNX3 and activating the downstream p53/p21 signaling. Our study revealed the role of circLARP4/miR-761/RUNX3/p53/p21 signaling in HCC progression, providing a potential survival predictor and therapeutic candidate for HCC.
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Affiliation(s)
- Zhiqiang Chen
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
| | - Xueliang Zuo
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
- Department of Gastrointestinal SurgeryThe First Affiliated HospitalYijishan Hospital of Wannan Medical CollegeWuhuChina
| | - Liyong Pu
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
| | - Yao Zhang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
| | - Guoyong Han
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
| | - Long Zhang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
| | - Jindao Wu
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingChina
| | - Xuehao Wang
- Hepatobiliary CenterThe First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Liver TransplantationChinese Academy of Medical SciencesNHC Key Laboratory of Living Donor Liver TransplantationNanjingChina
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Coluzzi E, Leone S, Sgura A. Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest. Cells 2019; 8:cells8010019. [PMID: 30609792 PMCID: PMC6356380 DOI: 10.3390/cells8010019] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 12/29/2018] [Indexed: 12/12/2022] Open
Abstract
Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this study, we wanted to understand the mechanisms by which oxidative damage causes telomere dysfunction and senescence in human primary fibroblasts. After acute oxidative stress at telomeres, our data demonstrated a reduction in TRF1 and TRF2, which are involved in proper telomere replication and T-loop formation, respectively. Furthermore, we observed a higher level of γH2AX with respect to 53BP1 at telomeres, suggesting a telomeric replication fork stall rather than double-strand breaks. To confirm this finding, we studied the replication of telomeres by Chromosome Orientation-FISH (CO-FISH). The data obtained show an increase in unreplicated telomeres after hydrogen peroxide treatment, corroborating the idea that the presence of 8-oxoG can induce replication fork arrest at telomeres. Lastly, we analyzed the H3K9me3 histone mark after oxidative stress at telomeres, and our results showed an increase of this marker, most likely inducing the heterochromatinization of telomeres. These results suggest that 8-oxoG is fundamental in oxidative stress-induced telomeric damage, principally causing replication fork arrest.
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Affiliation(s)
- Elisa Coluzzi
- Department of Science, University of Rome "Roma TRE", Viale Guglielmo Marconi, 446, 00146 Rome, Italy.
| | - Stefano Leone
- Department of Science, University of Rome "Roma TRE", Viale Guglielmo Marconi, 446, 00146 Rome, Italy.
| | - Antonella Sgura
- Department of Science, University of Rome "Roma TRE", Viale Guglielmo Marconi, 446, 00146 Rome, Italy.
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Zhou X, Zhang P, Han H, Lei H, Zhang X. Hypermethylated in cancer 1 (HIC1) suppresses bladder cancer progression by targeting yes-associated protein (YAP) pathway. J Cell Biochem 2018; 120:6471-6481. [PMID: 30417565 DOI: 10.1002/jcb.27938] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 10/02/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Bladder cancer (BCa) is the most common malignant tumor in the urinary system. Growing evidence suggests that as a tumor suppressor gene, hypermethylated in cancer 1 (HIC1) is correlated with various malignancies in the modulation of tumor progression. This study aims to investigate the effect of HIC1 on regulating the proliferation, migration, and invasion of BCa. METHODS Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to evaluate the expression of HIC1 messenger RNA and protein in human BCa tissues and cells. Proliferation, migration and invasion assays, and flow cytometry assay were performed to assess the biological functional role of HIC1 in BCa. Co-immunoprecipitation (Co-IP) examined the protein-protein interaction. The signaling pathways involved in the mode of action of HIC1 in BCa were also investigated. RESULTS HIC1 was found downregulated in tested samples. Cloning formation assay and cell-proliferation activity analysis showed that overexpression of HIC1 significantly inhibited the proliferation of BCa cells, while knockdown led to the opposite, namely the promotion of the proliferation. Flow cytometry assay confirmed the arrest of the cell cycle at the G1 phase with overexpression of HIC1 observed. Moreover, HIC1 inhibited migration and invasion of BCa. Co-IP showed the binding between YAP (yes-associated protein) and TEAD (TEA domain/transcription enhancer factor family members) as well as the cancerostatic activity of HIC1, partially manifested via its negative regulation of YAP signaling pathway. CONCLUSIONS Our data unprecedently showed that HIC1 was responsible for the inhibition of proliferation, migration, and invasion of BCa via the YAP signaling pathway. These findings suggested that therapeutic strategies regulating HIC1 expression might provide effective treatments for BCa.
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Affiliation(s)
- Xiaoguang Zhou
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Peng Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hu Han
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hongen Lei
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xiaodong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
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42
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Nishida N, Nishimura T, Kaido T, Minaga K, Yamao K, Kamata K, Takenaka M, Ida H, Hagiwara S, Minami Y, Sakurai T, Watanabe T, Kudo M. Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy. Cancers (Basel) 2018; 10:367. [PMID: 30274313 PMCID: PMC6210853 DOI: 10.3390/cancers10100367] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/25/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs were examined for TP53, CTNNB1, and TERT promoter mutation, methylation of 8 tumor suppressor genes, and 3 repetitive DNA sequences to estimate promoter hypermethylation and global hypomethylation. A fractional allelic loss (FAL) was calculated to represent chromosomal instability through microsatellite analysis. Molecular subclasses were determined using corresponding and hierarchical clustering analyses. Next, twenty-five HCC patients who underwent liver transplantation were analyzed for associations between molecular characteristics and metastatic recurrence; survival analyses were validated using a publicly available dataset of 376 HCC cases from the Cancer Genome Atlas (TCGA). An HCC subtype characterized by TP53 mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; CTNNB1 mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including TP53 mutation, high FAL, significant global hypomethylation, and absence of CTNNB1 mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (p = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (p = 0.0076). We concluded that molecular risks determined by common genetic and epigenetic alterations could predict metastatic recurrence after curative treatments, and could be a marker for considering systemic therapy for HCC patients.
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Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Takafumi Nishimura
- Department of Medical Oncology, Kitano Hospital, 2-4-20 Ohgi-machi, Kita-ku, Oaska 530-8511, Japan.
| | - Toshimi Kaido
- Division Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Karahara-cho, Syogoin, Sakyo-ku, Kyoto 606-8507, Japan.
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Kentaro Yamao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Mamoru Takenaka
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Toshiharu Sakurai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
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Sun N, Zhang J, Zhang C, Shi Y, Zhao B, Jiao A, Chen B. Using Illumina Infinium HumanMethylation 450K BeadChip to explore genome‑wide DNA methylation profiles in a human hepatocellular carcinoma cell line. Mol Med Rep 2018; 18:4446-4456. [PMID: 30221710 PMCID: PMC6172394 DOI: 10.3892/mmr.2018.9441] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 08/03/2018] [Indexed: 12/31/2022] Open
Abstract
Aberrant DNA methylation is the most common type of epigenetic alteration and is associated with many types of cancer. Although previous studies have provided a few novel DNA methylation markers in hepatocellular carcinoma (HCC), specific DNA methylation patterns and comparisons of the aberrant alterations in methylation between HCC and normal liver cell lines have not yet been reported. Therefore, in the present study the Illumina Infinium HumanMethylation 450K BeadChip was employed to identify the genome-wide aberrant DNA methylation profiles of Huh7 and L02 cells. Following Bonferroni adjustment, 102,254 differentially methylated CpG sites (covering 26,511 genes) were detected between Huh7 and L02 cells. Of those CpG sites, 62,702 (61.3%) sites were hypermethylated (covering 12,665 genes) and 39,552 (38.7%) sites were hypomethylated (covering 13,846 genes). The results of the present study indicated that 40.3% of the CpG sites were in CpG island regions, 20.7% were in CpG shores and 8.8% were in shelf regions. A total of 57.3% hypermethylated CpG sites and 39.4% of the hypomethylated CpG sites had a |β-Difference| ≥50%. Within the significant differentially methylated CpG sites, 490 genes were located within 598 differentially methylated regions. Gene Ontology enrichment analysis revealed that 2,107 differentially methylated genes were associated with ‘biological process’, 13,351 differentially methylated genes were associated with ‘molecular function’, and 18,041 differentially methylated genes were associated with ‘cellular component’. Kyoto Encyclopedia of Genes and Genomes pathway-based analysis revealed 43 signaling pathways that were associated with 5,195 differentially methylated genes. These results demonstrated that aberrant DNA methylation may be a key and common event underlying the tumorigenesis of Huh7 cells. The present study also identified many subsets of hypo- or hyper-methylated CpG sites, genes and signaling pathways, which have an importance in the occurrence and development of HCC.
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Affiliation(s)
- Ning Sun
- Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Jialin Zhang
- Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Chengshuo Zhang
- Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yue Shi
- Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Bochao Zhao
- Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Ao Jiao
- Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Baomin Chen
- Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Nakagama H, Ochiya T. Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells. Mol Ther 2018; 26:1840-1854. [PMID: 29759938 PMCID: PMC6035736 DOI: 10.1016/j.ymthe.2018.04.018] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/17/2018] [Accepted: 04/20/2018] [Indexed: 02/07/2023] Open
Abstract
Primary liver tumors are mainly represented by hepatocellular carcinoma (HCC), one of the most aggressive and resistant forms of cancer. Liver tumorigenesis is characterized by an accumulation of epigenetic abnormalities, leading to gene extinction and loss of hepatocyte differentiation. The aim of this work was to investigate the feasibility of converting liver cancer cells toward a less aggressive and differentiated phenotype using a process called epigenetic reconditioning. Here, we showed that an epigenetic regimen with non-cytotoxic doses of the demethylating compound 5-azacytidine (5-AZA) promoted an anti-cancer response by inhibiting HCC cell tumorigenicity. Furthermore, epigenetic reconditioning improved sorafenib response. Remarkably, epigenetic treatment was associated with a significant restoration of differentiation, as attested by the increased expression of characteristic hepatocyte markers in reconditioned cells. In particular, we showed that reexpression of these epigenetically silenced liver genes following 5-AZA treatment or after knockdown of DNA methyltransferase 1 (DNMT1) was the result of regional CpG demethylation. Lastly, we confirmed the efficacy of HCC differentiation therapy by epigenetic reconditioning using an in vivo tumor growth model. In summary, this work demonstrates that epigenetic reconditioning using the demethylating compound 5-AZA shows therapeutic significance for liver cancer and is potentially attractive for the treatment of solid tumors.
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Affiliation(s)
- Luc Gailhouste
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
| | - Lee Chuen Liew
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ken Yasukawa
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Izuho Hatada
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hitoshi Nakagama
- Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; National Cancer Center, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
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Lin H, Fan X, He L, Zhou D. Methylation patterns of RASA3 associated with clinicopathological factors in hepatocellular carcinoma. J Cancer 2018; 9:2116-2122. [PMID: 29937930 PMCID: PMC6010675 DOI: 10.7150/jca.24567] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/31/2018] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common tumor worldwide. The relationship between the gene methylation accumulation and HCC has been widely studied. In our study, we used the Sequenom EpiTYPER assay to investigate the methylation levels of the RASA3 in 164 HCC samples and paired adjacent non-cancerous tissues, and the association between methylation level and clinicopathological features. The methylation level of the RASA3 in HCC samples was found significantly lower than that in the adjacent non-cancerous tissues (P<0.0001). Moreover, the hypomethylation of RASA3 in HCC samples was connected with the presence of tumornecrosis (P=0.029) and alcohol intake (P=0.002). Furthermore, it was found that the expression of RASA3 was significantly decreased in tumor tissues (P=0.0053), which was also correlated with the methylation levels of RASA3 gene. Thus, RASA3 hypomethylation is a common feature in HCC, and may be a potential mechanism for HCC development, and serves as a useful biomarker for the early detection, especially in alcohol-associated HCCs.
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Affiliation(s)
- Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - LiFeng He
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Daizhan Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.,Present address: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine; Institute of Medical Genetics, Tongji University, Shanghai, China
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Erstad DJ, Fuchs BC, Tanabe KK. Molecular signatures in hepatocellular carcinoma: A step toward rationally designed cancer therapy. Cancer 2018; 124:3084-3104. [DOI: 10.1002/cncr.31257] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Derek J. Erstad
- Department of SurgeryMassachusetts General HospitalBoston Massachusetts
| | - Bryan C. Fuchs
- Division of Surgical OncologyMassachusetts General HospitalBoston Massachusetts
| | - Kenneth K. Tanabe
- Division of Surgical OncologyMassachusetts General HospitalBoston Massachusetts
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Wong CC, Li W, Chan B, Yu J. Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers. Semin Cancer Biol 2018; 55:90-105. [PMID: 29665409 DOI: 10.1016/j.semcancer.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development. As such, detection of aberrant DNA methylation is being developed as biomarkers for prognostic and diagnostic purposes in gastrointestinal cancers. Diverse tissue types are suitable for the analyses of methylated DNA, such as tumor tissues, blood, plasma, and stool, and some of these markers are already utilized in the clinical setting. Recent advances in the genome-wide epigenomic approaches are enabling the comprehensive mapping of the cancer methylome, thus providing new avenues for mining novel biomarkers for disease prognosis and diagnosis. Here, we review the current knowledge on DNA methylation biomarkers for the prognostication and non-invasive diagnosis of gastrointestinal cancers and highlight their clinical application.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bertina Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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Zhang C, Li J, Huang T, Duan S, Dai D, Jiang D, Sui X, Li D, Chen Y, Ding F, Huang C, Chen G, Wang K. Meta-analysis of DNA methylation biomarkers in hepatocellular carcinoma. Oncotarget 2018; 7:81255-81267. [PMID: 27835605 PMCID: PMC5348390 DOI: 10.18632/oncotarget.13221] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 11/01/2016] [Indexed: 12/14/2022] Open
Abstract
DNA methylation is an epigenetic mechanism in the pathogenesis of hepatocellular carcinoma (HCC). Here, we conducted a systematic meta-analysis to evaluate the contribution of DNA methylation to the risk of HCC. A total of 2109 publications were initially retrieved from PubMed, Web of Science, Cochrane Library, Embase, CNKI and Wanfang literature database. After a four-step filtration, we harvested 144 case-control articles in the meta-analysis. Our results revealed that 24 genes (carcinoma tissues vs adjacent tissues), 17 genes (carcinoma tissues vs normal tissues) and six genes (carcinoma serums vs normal serums) were significantly hypermethylated in HCC. Subgroup meta-analysis by geographical populations showed that six genes (carcinoma tissues vs adjacent tissues) and four genes (carcinoma tissues vs normal tissues) were significantly hypermethylated in HCC. Our meta-analysis identified the correlations between a number of aberrant methylated genes (p16, RASSF1A, GSTP1, p14, CDH1, APC, RUNX3, SOCS1, p15, MGMT, SFRP1, WIF1, PRDM2, DAPK1, RARβ, hMLH1, p73, DLC1, p53, SPINT2, OPCML and WT1) and HCC. Aberrant DNA methylation might become useful biomarkers for the prediction and diagnosis of HCC.
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Affiliation(s)
- Cheng Zhang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jinyun Li
- Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Tao Huang
- Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Shiwei Duan
- Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Dongjun Dai
- Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Danjie Jiang
- Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Xinbing Sui
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yidan Chen
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Fei Ding
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Changxin Huang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Gongying Chen
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Kaifeng Wang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
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Protein inhibitor of activated STAT 4 (PIAS4) regulates pro-inflammatory transcription in hepatocytes by repressing SIRT1. Oncotarget 2018; 7:42892-42903. [PMID: 27285989 PMCID: PMC5189995 DOI: 10.18632/oncotarget.9864] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/06/2016] [Indexed: 01/07/2023] Open
Abstract
Excessive nutrition promotes the pathogenesis of non-alcoholic steatohepatitis (NASH), characterized by the accumulation of pro-inflammation mediators in the liver. In the present study we investigated the regulation of pro-inflammatory transcription in hepatocytes by protein inhibitor of activated STAT 4 (PIAS4) in this process and the underlying mechanisms. We report that expression of the class III deacetylase SIRT1 was down-regulated in the livers of NASH mice accompanied by a simultaneous increase in the expression and binding activity of PIAS4. Exposure to high glucose stimulated the expression PIAS4 in cultured hepatocytes paralleling SIRT1 repression. Estrogen, a known NASH-protective hormone, ameliorated SIRT1 trans-repression by targeting PIAS4. Over-expression of PIAS4 enhanced, while PIAS4 knockdown alleviated, repression of SIRT1 transcription by high glucose. Lentiviral delivery of short hairpin RNA (shRNA) targeting PIAS4 attenuated hepatic inflammation in NASH mice by restoring SIRT1 expression. Mechanistically, PIAS4 promoted NF-κB-mediated pro-inflammatory transcription in a SIRT1 dependent manner. In conclusion, our study indicates that PIAS4 mediated SIRT1 repression in response to nutrient surplus contributes to the pathogenesis of NASH. Therefore, targeting PIAS4 might provide novel therapeutic strategies in the intervention of NASH.
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Mehra M, Chauhan R. Long Noncoding RNAs as a Key Player in Hepatocellular Carcinoma. BIOMARKERS IN CANCER 2017; 9:1179299X17737301. [PMID: 29147078 PMCID: PMC5673005 DOI: 10.1177/1179299x17737301] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major malignancy in the liver and has emerged as one of the main cancers in the world with a high mortality rate. However, the molecular mechanisms of HCC are still poorly understood. Long noncoding RNAs (lncRNAs) have recently come to the forefront as functional non-protein-coding RNAs that are involved in a variety of cellular processes ranging from maintaining the structural integrity of chromosomes to gene expression regulation in a spatiotemporal manner. Many recent studies have reported the involvement of lncRNAs in HCC which has led to a better understanding of the underlying molecular mechanisms operating in HCC. Long noncoding RNAs have been shown to regulate development and progression of HCC, and thus, lncRNAs have both diagnostic and therapeutic potentials. In this review, we present an overview of the lncRNAs involved in different stages of HCC and their potential in clinical applications which have been studied so far.
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Affiliation(s)
- Mrigaya Mehra
- Studio of Computational Biology & Bioinformatics, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur, India
- Academy of Scientific & Innovative Research, Chennai, India
| | - Ranjit Chauhan
- Department of Hepatology, Loyola University Chicago, Chicago, IL, USA
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Health Sciences Center, Memorial University, St John’s, Newfoundland and Labrador, Canada
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