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Grant Details

Grant Number: 5R03CA156629-02 Interpret this number
Primary Investigator: Shen, Jing
Organization: Columbia University Health Sciences
Project Title: Aberrant DNA Methylation of Microrna Genes in Hepatocellular Carcinoma (HCC)
Fiscal Year: 2012


DESCRIPTION (provided by applicant): Tumor suppressor gene silencing by promoter DNA methylation is an important mechanism of tumorigenesis, including in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs), as key regulators of gene expression, play a critical role in cell proliferation, differentiation and apoptosis. Tumor suppressive miRNAs harboring CpG-islands in their promoter regions may also be sensitive to methylation-mediated silencing. Previous studies found that the deregulated expression of tumor suppressive miRNAs (miR-1-1, miR-124, and miR-203) might be due to aberrant DNA methylation. These limited data were obtained from different animal models, cancer cell lines or from a study of a small number of frozen tumor tissues. The methylation status of many miRNAs with tumor suppressive functions is largely unknown, especially for those specifically expressed in liver tissues (miR-122, miR-152, miR-194, miR-199 and miR-215). Our hypothesis is that DNA methylation in tumor suppressive miRNA genes is a common event influencing relevant mature miRNA expression, and contributes to differentiate HCC tumor and non-tumor tissues. The two specific aims are: (1) To examine whether a panel of tumor suppressive miRNA genes have significantly higher levels of DNA methylation in HCC tumor tissues compared with adjacent non-tumor tissues, and test whether the miRNA methylation levels are different for hepatitis B virus (HBV) and hepatitis C virus (HCV)-related HCC; (2) To examine whether a subgroup of miRNA genes showing significant methylation alterations are associated with the down-regulation of relevant mature miRNA expression. A case-only study will be conducted using a well-established, formalin- fixed, paraffin-embedded (FFPE) tissue bank of US HCC patients at Columbia University Medical Center. Totally, 120 histologically confirmed HCC cases with tumor and adjacent non-tumor tissues and HBV/HCV infection data are available for the current study. This pilot study will provide valuable preliminary data to understand the role of miRNA gene methylation in distinguishing HCC malignant tissue from non-tumor tissues. These methylation markers have potential clinical applications to improve risk assessment, early diagnosis and prognostic prediction, and may even possibly improve treatment because of the reversible nature of epigenetic changes. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


Telomere Length and Risk of Hepatocellular Carcinoma: A Nested Case-control Study in Taiwan Cancer Screening Program Cohort.
Authors: Zeng H. , Wu H.C. , Wang Q. , Yang H.I. , Chen C.J. , Santella R.M. , Shen J. .
Source: Anticancer research, 2017 02; 37(2), p. 637-644.
PMID: 28179311
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Evaluating normalization approaches for the better identification of aberrant microRNAs associated with hepatocellular carcinoma.
Authors: Shen J. , Wang Q. , Gurvich I. , Remotti H. , Santella R.M. .
Source: Hepatoma research, 2016 Nov; 2, p. 305-315.
EPub date: 2016-11-18.
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Plasma Adiponectin and Hepatocellular Carcinoma Survival Among Patients Without Liver Transplantation.
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Source: Anticancer research, 2016 10; 36(10), p. 5307-5314.
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Identifying microRNA panels specifically associated with hepatocellular carcinoma and its different etiologies.
Authors: Shen J. , Siegel A.B. , Remotti H. , Wang Q. , Santella R.M. .
Source: Hepatoma research, 2016 Jun; 2, p. 151-162.
EPub date: 2016-06-01.
PMID: 28243631
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Exploration of Deregulated Long Non-Coding RNAs in Association with Hepatocarcinogenesis and Survival.
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Source: Cancers, 2015-09-10; 7(3), p. 1847-62.
EPub date: 2015-09-10.
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Integrative epigenomic and genomic filtering for methylation markers in hepatocellular carcinomas.
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Source: BMC medical genomics, 2015-06-10; 8, p. 28.
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Genome-Wide Expression of MicroRNAs Is Regulated by DNA Methylation in Hepatocarcinogenesis.
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Source: Gastroenterology research and practice, 2015; 2015, p. 230642.
EPub date: 2015-03-11.
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Exploration of genome-wide circulating microRNA in hepatocellular carcinoma: MiR-483-5p as a potential biomarker.
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Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2013 Dec; 22(12), p. 2364-73.
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Exploring genome-wide DNA methylation profiles altered in hepatocellular carcinoma using Infinium HumanMethylation 450 BeadChips.
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Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma.
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