Functional Genomics on the Mechanisms Regulating Tissue Homeostasis and Tumor Development: Identification and Characterization of Ptprf

Growth suppression during cell proliferation is essential for tissue homeostasis. Evasion of growth suppression leads to hyperproliferation and tumor initiation. However, little is known about how cells elicit suppression signls during proliferation and how cancer cells evade growth suppression. To elucidate the mechanism, we have developed a loss-of-function screening for genomewide screening of genes regulating growth suppression during proliferation and and suppressing tumor initiation. We have identified 29 tumor suppressor genes. Of them, the protein tyrosine phosphatase receptor type F (PTPRF) was selected for further characterization, because our preliminary data showed that PTPRF might play a crucial role in growth suppression during cell proliferation. PTPRF was induced during proliferation. Subsequently, the induced PTPRF quenched the activated proliferation signals to prevent cell hyperproliferation and tumor formation in vitro and in vivo. Interestingly, PTPRF was frequently downregulated in human hepatoma. High expression of PTPRF was noted in the gastric and colonic mucosal epithelial cells. We thus hypothesize that PTPRF plays a significant role in maintaining tissue homeostasis and preventing tumor initiation. PTPRF potentially plays a critical role in human carcinogenesis particularly in tissues with chronic injury or inflammation, including chronic hepatitis, gastritis, and colitis. We thus set forther to examine these hypothesis with the following specific aims to be accomplished in this project: 1) Functional genomics screening for genes essential for growth suppression during proliferation and functioning as suppressors for tumor intiation (1st yr) 2) the mechanisms whereby cell-cell contact induces PTPRF expression (1st – 2nd yr) 3) the mechanisms whereby PTPRF eliciting signals to arrest proliferation (1st yr) 4) clinical significance of PTPRF in human carcinogenesis including liver, gastric, colorectal, and pancreas cancer; the mechanisms leading to loss-of-function of PTPRF (1st – 2rd yr) 5) establishment of gene knockout mice (1st – 3rd yr) 6) Study on the role of PTPRF in liver and colorectal cancer development (3rd yr and beyond) Elucidation of the mechanisms of growth suppression during proliferation and the critical pathways that orchestrate tumor initiation will provide new and critical targets of anti-cancer therapies.

Project ID:PC10401-1134
External Project ID:MOST103-2314-B182-019-MY3