The ying/yang relationship of differentiation versus proliferation is a fundamental tenet in the development of multicellular organisms, as well as the basis for cancer. Transcription factors (TFs), such as nuclear receptors (NRs), regulate the genes responsible for carrying out these cellular processes. HNF4? is a highly conserved member of the NR superfamily of ligand dependent TFs. During the past 20+ years, HNF4? has been well characterized for its role in early development, liver differentiation and an inherited form of diabetes (MODY1). More recently, a role for HNF4? has emerged in the intestine/colon and several links to cancer have been reported. Intriguingly, the role for HNF4? in cancer seems to depend on the particular isoform of HNF4?: there are nine isoforms driven by two alternative promoters, P1 and P2. Here, we propose to follow up on the results from the previous round of funding in which we identified the mechanism responsible for differential regulation of the P1- and P2-driven HNF4? isoforms in human colon cancer. That mechanism involves the oncogene Src tyrosine kinase and is impacted by single nucleotide polymorphisms (SNPs) in the HNF4? gene. We will pursue the following three Specific Aims: 1) Determine the role of the P1- versus P2- HNF4? isoforms in the colon by using mouse models, human culture models and human tissue analysis;2) Determine the role of P2- HNF4? in liver cancer and development by using mouse models and cutting edge "-omic" approaches to decipher the molecular basis for the differences in the isoforms;and 3) Elucidate the effects of the Src tyrosine kinase pathway on HNF4? using mouse and human models. The proposed experiments will provide invaluable insights not just into the molecular mechanisms of cancer but also into the dichotomy between the differentiation and proliferation and molecular mechanisms of nuclear receptor action. They will generate results that could be of use in the clinic to help properly diagnose and treat liver and colon cancer.
While cancer death rates decreased in the U.S between 2004 and 2009, certain cancers remain very prevalent and cause large numbers of deaths. Others cancers have increased rates of incidence and yet the survival rates remain very low. For example, colorectal cancer is the third most deadly cancer in the U.S., claiming >50,000 deaths every year. And, the incidence of liver cancer, which has the second lowest survival rate (~15%), is actually increasing. Major risk factors for liver cancer are viral infections that cause hepatitis (e.g., HBV and HCV) as well as the metabolic syndrome that is associated with obesity and diabetes. Colon cancer is also directly impacted by diet. Obesity and diabetes have increased in the U.S. and worldwide to epidemic proportions with more than 55% of adult Americans classified as obese. This proposal examines the role of a gene, HNF4?, in both colon and liver in normal tissue and cancer. The ultimate goal is a better understanding of how these cancers progress so that we can eventually develop better methods of treating them.
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