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.
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.
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