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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA140861-04
Application #
8324002
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2009-09-25
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$143,927
Indirect Cost
$10,661
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Fuchs, Bryan C; Hoshida, Yujin; Tanabe, Kenneth K (2015) Reply: To PMID 24677197. Hepatology 61:729-30
Motola, Daniel L; Caravan, Peter; Chung, Raymond T et al. (2014) Noninvasive Biomarkers of Liver Fibrosis: Clinical Applications and Future Directions. Curr Pathobiol Rep 2:245-256
Fuchs, Bryan C; Hoshida, Yujin; Fujii, Tsutomu et al. (2014) Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology 59:1577-90
Fuchs, Bryan C; Wang, Huifang; Yang, Yan et al. (2013) Molecular MRI of collagen to diagnose and stage liver fibrosis. J Hepatol 59:992-8
Yamada, S; Kuroda, T; Fuchs, B C et al. (2012) Oncolytic herpes simplex virus expressing yeast cytosine deaminase: relationship between viral replication, transgene expression, prodrug bioactivation. Cancer Gene Ther 19:160-70
Abu Dayyeh, Barham K; Yang, May; Fuchs, Bryan C et al. (2011) A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology 141:141-9
Fujii, Tsutomu; Fuchs, Bryan C; Yamada, Suguru et al. (2010) Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol 10:79