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Fellow: Dr. Andres Matoso
Mentor: Dr. Alexander Nikitin
Contact Information: E-mail: an58@cornell.edu - Phone: 607-253-4347
Sponsor: Ovarian Cancer Research Fund
Grant Number: CUMC/POE02.06
Title: Mechanisms of Met Regulation by p53 in Ovarian Cancer
Annual Direct Cost: $75,000
Project Period: 12/31/06-12/31/07
DESCRIPTION (provided by applicant): Understanding the molecular and cellular mechanisms of ovarian carcinogenesis is the long-term goal of our research. Among the most common genetic alterations in human sporadic EOC are p53 mutations, defective pl6/retinoblastoma (Rb) pathways and aberrant MET signaling. All of these alterations, as well as hypoxia, have been reported to be unfavorable prognostic factors. Hypoxia-inducible factor-1 (HIF-1) is the major transcriptional factor specially activated by hypoxia and its stability has been shown to be regulated by p53. Recently, we have established the first genetically-defined model of EOC based on ovarian surface epithelium (OSE)-specific Inactivation of p53 and Rb. In this model, neoplasms closely resemble human ovarian serous adenocarcinoma, and frequently contain hypoxic areas. Our recent results show that acute inactivation of p53 leads to increased expresslon of Met followed by increase in motility and invasion properties of OSE cells in cell culture. In cervical carcinoma xenografts and human breast tumors, MET protein levels are highly up-regulated in hypoxic areas. This regulation has been shown to be transcriptional and is mediated by two HIF-1 binding sites and an AP-1 site. At the same time, specific contributions of p53 and HIF-1 towards MET-mediated motility and invasion during EOC progression remain uncertain. We hypothesize that p53 inactivation may result in release of transcriptional repression of the MET promoter and further capacitate its activation by HIF-1 up-regulation. To test this hypothesis we propose the following Aims: Aim 1. To determine the regulation of MET promoter by p53. Aim 2. To evaluate the effect of p53 on hypoxia-regulated HIF-I activity. Aim 3. To establish the effect of HIF-1 on hypoxia-regulated MET expression. These studies should advance the understanding of the EOC pathogenesis by dissecting a novel mechanism by which defective p53 pathway additionally facilitates the course of neoplastic progression and by establishing the role of HIF-1/MET signaling during the OSE carcinogenesis.
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