The long term objective is to advance our understanding of the role of dietary deficiency of the methyl donors in epigenetic regulation of gene expression in hepatocarcinogenesis. In the last granting period, we showed that the gene encoding protein tyrosine phosphatase O (PTPRO) is methylated and silenced in preneoplastic nodules and primary hepatomas induced in a rat model. Subsequent study established that PTPRO is a bona fide tumor suppressor. In the present study we will examine whether its promoter methylation can be used as biomarker for liver cancer of specific etiology and its function in liver. We will also explore epigenetic regulation of nutrient gene interaction in hepatocarcinogenesis using methionine adenosytransferase 1a (Mat1a) null (MAT1KO) mice and methyl deficient diet as a model system. Frequent loss of Mat1a in human primary liver tumors results in decreased SAM (cofactor for all methylation reactions) level and correlates with dedifferentiation of hepatocytes. MAT1KO mice exhibit reduced hepatic SAM level and increased susceptibility to hepatic injury upon feeding methyl-deficient diet.
The specific aims of the proposal are: 1) to analyze methylation profile of PTPRO CpG island spanning the promoter and exon1 in a large number of human primary HCCs of different etiology using EpiTyper technology, and determine whether methylation of PTPRO in HCCs inversely correlates with its expression. 2) Determine the potential role of PTPRO in regulating invasiveness of HCC cells and their sensitization to drug (doxorubicin, 5-Fluorouracil)-induced apoptosis, and identify liver-specific substrate(s) of PTPRO by substrate-trapping assay that will unravel potential therapeutic targets for HCC. 3) Investigate liver pathophysiology and susceptibility to hepatocarcinogenesis of MAT1KO mice on CDAA diet compared to the wild type mice. 4) Compare methylation profile of the liver genome of MAT1KO mice with the wild type mice at early stages of CDAA diet-induced hepatocarcinogenesis, confirm differential methylation of the candidate genes and determine whether methylation status of these genes correlates inversely with their expression. It is hoped that this study will provide us with novel insights into (a) role of PTPRO in liver tumorigenesis, (b) relationship between dietary methyl deficiency and changes in DNA methylation and expression of genes at early stages of hepatocarcinogenesis, (c) role of Mat1a and SAM in induction of liver cancer by the deficient diet and (d) additional molecular targets for early stage diagnosis and epigenetic therapy of HCC. This proposal also fits well with the recent program announcement of multiple institutes on diet, epigenetic events and cancer prevention.Liver cancer is the fifth most prevalent cancer in the world and is the third leading cause of cancer-related death with annual date rate exceeding 500,000, and is increasing in frequency and mortality (particularly in men) in the United States. The present study will address the role of dietary methyl deficiency in the initiation of liver tumorigenesis. Specifically, this study is aimed at (a) elucidation of the role of specific genes that are methylated and silenced at early stages of liver cancer in response to this dietary deficiency and (b) identification of novel molecular targets for early diagnosis and epigenetic therapy of liver cancer. This proposal also fits well with the recent program announcement of multiple institutes on diet, epigenetic events and cancer prevention.

Public Health Relevance

Liver cancer is the fifth most prevalent cancer in the world and is the third leading cause of cancer-related death with annual date rate exceeding 500,000, and is increasing in frequency and mortality (particularly in men) in the United States. The present study will address the role of dietary methyl deficiency in the initiation of liver tumorigenesis. Specifically, this study is aimed at (a) elucidation of the role of specific genes that are methylated and silenced at early stages of liver cancer in response to this dietary deficiency and (b) identification of novel molecular targets for early diagnosis and epigenetic therapy of liver cancer. This proposal also fits well with the recent program announcement of multiple institutes on diet, epigenetic events and cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086978-10
Application #
8196850
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Seifried, Harold E
Project Start
2000-07-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
10
Fiscal Year
2012
Total Cost
$293,052
Indirect Cost
$97,684
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Reyes, Ryan K; Motiwala, Tasneem; Jacob, Samson T (2014) Regulation of glucose metabolism in hepatocarcinogenesis by microRNAs. Gene Expr 16:85-92
Wang, Bo; Hsu, Shu-hao; Wang, Xinmei et al. (2014) Reciprocal regulation of microRNA-122 and c-Myc in hepatocellular cancer: role of E2F1 and transcription factor dimerization partner 2. Hepatology 59:555-66
Hsu, Shu-hao; Motiwala, Tasneem; Roy, Satavisha et al. (2013) Methylation of the PTPRO gene in human hepatocellular carcinoma and identification of VCP as its substrate. J Cell Biochem 114:1810-8
Motiwala, Tasneem; Zanesi, Nicola; Datta, Jharna et al. (2011) AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia. Blood 118:6132-40
Wang, Bo; Jacob, Samson T (2011) Role of cancer stem cells in hepatocarcinogenesis. Genome Med 3:11
Majumder, Sarmila; Alinari, Lapo; Roy, Satavisha et al. (2010) Methylation of histone H3 and H4 by PRMT5 regulates ribosomal RNA gene transcription. J Cell Biochem 109:553-63
Ghoshal, Kalpana; Motiwala, Tasneem; Claus, Rainer et al. (2010) HOXB13, a target of DNMT3B, is methylated at an upstream CpG island, and functions as a tumor suppressor in primary colorectal tumors. PLoS One 5:e10338
Motiwala, Tasneem; Datta, Jharna; Kutay, Huban et al. (2010) Lyn kinase and ZAP70 are substrates of PTPROt in B-cells: Lyn inactivation by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib. J Cell Biochem 110:846-56
Majumder, Sarmila; Roy, Satavisha; Kaffenberger, Thomas et al. (2010) Loss of metallothionein predisposes mice to diethylnitrosamine-induced hepatocarcinogenesis by activating NF-kappaB target genes. Cancer Res 70:10265-76
Wang, B; Hsu, S-H; Majumder, S et al. (2010) TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene 29:1787-97

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