The central focus of this proposal is to understand molecular mechanisms of focal adhesion kinase (FAK) in promoting hepatocarcinogenesis. Hepatocellular carcinoma (HCC) causes more than 600,000 deaths worldwide and 12,000 deaths in United States per year. The overall survival of patients with HCC is less than 12% and most patients with HCC have limited treatment options. The pathogenic mechanisms underlying HCC are not fully known. Understanding the molecular signaling pathways that drive or mediate the development of HCC is important for the identification of novel therapeutic targets for preventing and treating HCC. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many HCC specimens, however, the role of FAK in HCC has not be fully elucidated. Studying the role of FAK in hepatocarcinogenesis is critical to determine whether FAK is a suitable candidate target for treating HCC and to identify potential points for therapeutic intervention to target FAK. We recently found that deletion of Fak in hepatocytes suppresses tumor proliferation and development, and prolongs survival in a c-Met (MET)/-catenin (CAT)-driven HCC mouse model. Our data suggest that inhibition of FAK may be a promising strategy to treat HCC. However, further studies are needed to more fully define the molecular mechanisms of FAK in promoting hepatocarcinogenesis. In this project, we will evaluate the role of FAK in HCC initiation and maintenance (Aim 1.1). This information will be important to determine the optimal timing of FAK inhibition to interrupt the development of HCC. In addition, we will determine whether kinase activity and scaffolding functions of FAK are necessary for hepatocarcinogenesis (Aim 1.2), which will provide information about how to target FAK (through its kinase activity and/or kinase-independent functions) to treat HCC. Furthermore, we will define whether overexpression of FAK can substitute for MET or CAT to induce HCC (Aim 2.1). The information will provide insight into which populations of HCC patients are suitable for targeting FAK. Finally, we will delineate the molecular mechanisms by which FAK regulates MET or CAT signaling to promote HCC (Aim 2.2). The information will provide new and critical insights into FAK's mechanism of action in HCC development. Overall, the results from these studies will provide important new understanding of the mechanisms of FAK in hepatocarcinogenesis, which is critical for targeting FAK to treat HCC.
Hepatocellular carcinoma (HCC) is a major human malignancy, largely incurable and in need of additional therapeutic approaches. We recently found that deletion of Fak in hepatocytes suppresses tumor proliferation and development, and prolongs survival of animals in a c-Met (MET)/-catenin (CAT)-driven HCC mouse model. In this project, we will define the molecular mechanisms of FAK in promoting hepatocarcinogenesis. The results from this project will provide new insight into molecular mechanisms of mechanisms of FAK in hepatocarcinogenesis, understanding of which is critical for targeting FAK to treat HCC.
| Shang, Na; Bank, Thomas; Ding, Xianzhong et al. (2018) Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation. Cell Death Dis 9:558 |
| Shang, Na; Arteaga, Maribel; Chitsike, Lennox et al. (2016) FAK deletion accelerates liver regeneration after two-thirds partial hepatectomy. Sci Rep 6:34316 |
| Shang, Na; Arteaga, Maribel; Zaidi, Ali et al. (2016) FAK Kinase Activity Is Required for the Progression of c-MET/?-Catenin-Driven Hepataocellular Carcinoma. Gene Expr 17:79-88 |
| Arteaga, Maribel; Shang, Na; Ding, Xianzhong et al. (2016) Inhibition of SIRT2 suppresses hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 310:G1155-68 |
