HEPATIC CARCINOGENESIS: MOLECULAR MECHANISMS

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DESCRIPTION (provided by applicant): Hepatocellular carcinoma is one of the most prevalent tumors worldwide. Differentiated hepatocytes are quiescent yet have the ability to proliferate in response to hepatocellular injury, partial hepatectomy and growth mediators, such as transforming growth factor alpha (TGFalpha). Although TGFalpha is a potent inducer of hepatocyte proliferation and liver tumorigenesis, the molecular mechanisms responsible for the effects of this cytokine are only partially understood. Increased transcriptional activity through phosphorylations of rat, chicken or human C/EBPbeta is induced by stimulators of cell proliferation. We have reported that primary hepatocytes isolated from C/EBPbeta-/-, but not from C/EBPbeta+/+, mice fail to proliferate in response to TGFalpha. The long-term objectives of this application are to understand the molecular mechanisms responsible for the development of hepatocellular carcinoma. The specific aim is to analyze the role of a site-specific phosphorylation of C/EBPbeta (Thr217) on the development of hepatocellular carcinoma. The presence of phosphorylated C/EBPbeta in human hepatocellular carcinoma will be determined with specific antibodies against this epitope. Similarly, gain-of-function mutations of the C/EBP? phosphorylation site (conserved in humans) could contribute to the pathogenesis of liver tumors in patients with chronic liver diseases. In addition, the PI will receive intensive training in the state-of-the-art genetics, pathophysiological and clinical aspects of hepatocellular carcinoma, as well as research presentations and the reviewing of grants and manuscripts.