The dramatic increase in recent years in the incidence of non-alcoholic fatty liver disease in the Western world has led to an increase in the prevalence of NASH (non-alcoholic steatohepatitis) and associated complications such as cirrhosis and hepatocellular cancer (HCC). In USA, NASH is emerging as a major risk factor for HCC with no effective therapy. Unlike HBV/HCV-induced HCC, very little is known about the mechanism(s) underlying the pathogenesis of NASH-associated HCC. We have used a mouse model of HCC in which 100% mice fed choline-deficient and amino acid defined (CDAA) diet develop NASH by 22 weeks and spontaneous HCC in ~75% mice by 65-75 weeks. Further, these mice exhibit well-defined pathological changes that are markedly similar to the progression of HCC in humans. A key finding from our study is the consistent upregulation of miR-155, a proinflammatory microRNA, from an early stage of feeding CDAA diet that correlates with development of NASH. Notably, miR-155 is elevated in human NASH and HCC patients and its level is an independent predictor of poor prognosis and recurrence-free survival in HCC patients. We hypothesize that upregulation of miR-155 in hepatocytes and Kupffer cells (inflammatory cells in the liver), plays a causal role in NASH and HCCs. This proposal is based on the novel findings that (i) miR-155 knockout (KO) mice exhibit reduced inflammation and triglyceridemia as early as 4 weeks of feeding CDAA diet, and (ii) zerumbone (ZER), a sesquiterpine phytochemical from an edible ginger suppressed both spontaneous and diet-induced inflammatory responses in mice and HCC cell growth in culture and caused downregulation of miR-155. To test our hypothesis that manipulation of miR-155 levels and treatment with ZER will inhibit NASH and HCC, we will pursue the following 3 aims. 1 (a) Elucidate the role of miR-155 in initiation and progression of diet-induced NASH and HCC using miR155KO mice, and (b) identify the underlying mechanism by focusing on miR-155 targets. 2 (a) Investigate the susceptibility of mice overexpressing miR-155 in hepatocytes or in hepatocytes+Kupffer cells to diet induced NASH and HCC, and (b) elucidate the underlying mechanism of differential pathogenesis by identifying its cell type specific targets. 3. Explore preventive/therapeutic potential of ZER by (a) assessing its anti-tumorigenic potential against HCC cells, (b) testing its anti-inflammatory function in mice, and (c) elucidating the molecular basis of its function.

Public Health Relevance

The dramatic increase in the incidence of hepatocellular cancer (HCC), particularly non- alcoholic steatohepatitis (NASH)-induced HCC in the United States, its dismal prognosis and poor response to current treatment regimens warrant the urgent need for new treatments for this cancer. Understanding the role of miR-155, the proinflammatory microRNA in inducing NASH-mediated HCC and the role of the anti-inflammatory phytochemical zerumbone in preventing inflammation is likely to lead to development of novel therapeutic approaches. Any improvement in therapeutic strategies based on novel mechanistic studies and preclinical trials in mouse models proposed here, would be an important step towards fighting Nonalcoholic Fatty Liver disease epidemics and the fatal liver cancer, the third leading cause of cancer related death worldwide.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Seifried, Harold E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 33 publications