The Role of EGF in Human Hepatocellular Transformation

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Overexpression of epidermal growth factor (EGF) in the liver induces transformation to hepatocellular carcinoma (HCC) in animal models. A single nucleotide polymorphism (A to G transition at position 61) has been identified in the EGF gene. We have demonstrated increased mRNA stability of the G allele both in hepatoma cell lines and primary human hepatocytes which may serve as a mechanism by which individuals with the G/G genotype have increased serum and liver tissue levels. Our analysis of the distribution of allelic frequencies in cirrhosis populations from both Massachusetts and France revealed that the G/G genotype was significantly associated with risk of HCC relative to the A/A genotype. Currently, the source of excess EGF is unknown. The majority of HCCs develop in the setting of cirrhosis. Therefore, the goal of Specific Aim 1 is to investigate the effects of cirrhosis on EGF expression in serum and the various liver cell populations as monitoring of EGF levels could be used to identify cirrhosis patients at high-risk for HCC. HCC is increasing in incidence both in the United States and worlwide. Given the lack of successful treatment options for HCC, chemoprevention in high-risk patients has been proposed as an alternative strategy. Exceedingly little is known about the molecular pathways leading to hepatocellular transformation. Therefore, the goal of Specific Aim 2 is to examine the signaling pathways initiated during EGF-induced transformation as a means to identify potential therapeutic targets. Small molecule EGF receptor (EGFR) tyrosine kinase inhibitors have proven effective as chemopreventive agents in a rat model of HCC. The goal of Specific Aim 3 is to identify resistance mechanisms in the residual tumors in order to design more effective chemoprevention strategies. The broad long-term objective of this proposal is to develop chemopreventive therapies that can be used to lower EGF levels and/or inhibit EGF-induced hepatocellular transformation. The data obtained from these experiments have broad implications as overexpression of the EGFR is a common event in neoplastic transformation, and we hypothesize that targeting of the EGF pathway may be a novel strategy for chemoprevention. RELEVANCE (See instructions): Novel and effective screening and treatment options are urgently needed for the diagnosis and prevention of liver cancer. Here we will analyze liver and serum EGF levels as a novel technique to monitor risk of liver cancer and also study the mechanisms by which EGF induces carcinogenesis. Further, the EGFR tyrosine kinase inhibitor, eriotinib, will be tested for its efficacy as a chemoprevention strategy for liver cancer.