A Novel Regulator of Pl-3-Kinase in Human Liver Cancer

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The molecular mechanisms underlying HCC development are not well characterized;however, the phosphatidylinositol-3-kinase (PI3K) pathway is dysfunctional in HCC tumors. PI3K generates a key lipid second messenger PI(3,4,5)P3 (PIP3) which activates signaling proteins and triggers cell survival, proliferation and motility. PI3K is composed of a p85 regulatory subunit and a p110 catalytic subunit. During the previous funding period, we characterized a novel negative regulator of PI3K we named PI3K interacting protein 1 (PIK3IP1). This protein shares a region of homology with p85 and binds to and down regulates p110 in vitro and in vivo. We determined that PIK3IP1 expression is reduced in human HCC. We also discovered that over expression of PIK3IP1 in hepatocytes suppresses HCC development in a mouse model of liver tumorigenesis by limiting hepatocyte proliferation. We propose to build on these studies in this application which is written in response to PA08-243 entitled, "Etiology, Prevention, and Treatment of Hepatocellular Carcinoma," and to the "Action Plan for Liver Disease Research." Our hypothesis to be tested in this renewal application is that PIK3IP1 is a key suppressor of PI3K signaling and, as such, its downregulation promotes liver cell growth and hepatic tumorigenesis. Based on our findings, we outline two rigorous specific aims to accomplish our task: Aim 1-to examine the consequences of PIK3IP1 loss on liver tumorigenesis in a PIK3IP1 liver specific knock out mouse model and interrogate the molecular mechanisms involved. Aim 2-to assess the molecular regulation of PIK3IP1 protein. Together, these studies should provide insight into the importance of PIK3IP1 negative regulation of PI3K to liver tumorigenesis.