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.
Liver cancer also known as hepatocellular carcinoma (HCC) is a major cause of cancer related death worldwide. Liver cancer is caused by viruses that infect liver cells and by consumption of alcohol. It is nearly impossible to treat: once a patient is diagnosed, it is unlikely that they will survive five years despite treatment. Thus new kinds of therapy that are potent at killing tumor cells but not the normal tissues of the body are needed. We study a pathway that signals inside cells called the PI3K pathway. It is linked to liver cancer. We have discovered a new protein called PIK3IP1 that modulates this pathway. When over expressed in the livers of mice, PIK3IP1 protects them from getting liver cancer. Now, we will study what happens when PIK3IP1 is absent from the liver. Will the mice get more liver tumors at a faster rate? Also, we will try to understand how the PIK3IP1 protein is regulated and how it controls the PI3K pathway using molecular biology methods. It is hoped new insights to treating liver tumors will arise from these studies.
| DeFrances, Marie C; Debelius, Daniel R; Cheng, Jing et al. (2012) Inhibition of T-cell activation by PIK3IP1. Eur J Immunol 42:2754-9 |
| He, Xin; Zhu, Zhenqi; Johnson, Carla et al. (2008) PIK3IP1, a negative regulator of PI3K, suppresses the development of hepatocellular carcinoma. Cancer Res 68:5591-8 |
| Zhu, Zhenqi; He, Xin; Johnson, Carla et al. (2007) PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein. Biochem Biophys Res Commun 358:66-72 |
