Hepatocellular carcinoma show the highest relative-risk increase as a consequence of obesity compared to some other common forms of cancer. Recent studies have established that obesity is an endocrine disorder and its endocrine effects are mediated by the adipocytokines. Adiponectin, an adipocytokine proposed to have therapeutic potential, is inversely associated with obesity. Importantly, lower levels of serum adiponectin are associated with high risk of cancers such as endometrial, breast, gastric, colorectal cancer. My preliminary studies show that adiponectin inhibits proliferation, induces apoptosis and activates AMPK in hepatocellular carcinoma cells. Hypothesis: An integral part of the progression of hepatocellular carcinoma is the acquisition of the invasive and metastatic properties. This proposal will examine the hypothesis that adiponectin suppresses the growth and metastatic potential of hepatocellular carcinoma cells by increased crosstalk between AMPK and LKB1-TSC2-mTOR pathway. Objectives: (1) To demonstrate that adiponectin inhibits metastatic properties of hepatocellular carcinoma. 2) To elucidate the potential signal-transduction mechanisms involved in adiponectin action. 3) To examine whether adiponectin inhibits hepatocellular carcinoma tumorigenesis in nude mice. Study design: The inhibition of metastatic potential of hepatocellular carcinoma cell line HepG2 by adiponectin will be analyzed using various growth, invasion, migration and anoikis assays. The signal transduction pathway involved in the biological function of adiponectin involves AMPK activation. Both upstream and downstream components of this pathway will be elucidated using kinase assays, western blotting, RT-PCR analysis. Selective inhibition using siRNA silencing will be used to define the function of adiponectin receptors. Tumor Xenograft [sic] model using athymic nude mice with HepG2 cells will be utilized to show the protective role of adiponectin in vivo. Relevance to public: Obesity, a major health problem in US is a significant risk factor for hepatocellular carcinoma and its endocrine effects are mediated by adipocytokines. The studies proposed here are designed to establish adiponectin as a novel negative regulator of hepatocellular carcinoma and systemically delineate the signaling mechanisms involved in its action. Delineation of the protective role of adiponectin in hepatocellular carcinoma thus presents new preventive and therapeutic options for patients.
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