Studies on Hepatocellular Carcinoma (HCC)：I. Liver Fatty Acid-Binding Protein (L-FABP) Promotes Cellular Angiogenesis and Migration in Hepatocellular CarcinomaII. Corosolic Acid Inhibits Hepatocellular Carcinoma Cell Migration by Targeting the VEGFR2/Src/FAK Pathway

• Main Authors: Chung-Yu Ku, 辜琮祐
• Other Authors: Jung-Yaw Lin
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/e2c7f8

博士 === 國立臺灣大學 === 生物化學暨分子生物學研究所 === 103 === Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of cancer death worldwide. The progression of HCC relies on the formation of new blood vessels, and VEGF is critical in this process. Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and its expression level was positively correlated with that of VEGF-A. Additionally, L-FABP significantly promoted tumor growth and metastasis in a xenograft mouse model. We also studied the mechanisms of L-FABP activity in tumorigenesis: L-FABP was found to be associated with VEGFR2 on membrane rafts and subsequently activate the Akt/mTOR/P70S6K/4EBP1 and Src/FAK/cdc42 pathways. This resulted in up-regulation of VEGF-A expression accompanied by an increase in both angiogenic potential and migration activity. Taken together, our results suggest that L-FABP may be a potential target for HCC chemotherapy. Inhibition of VEGFR2 activity has been proposed as an important strategy for the clinical treatment of hepatocellular carcinoma (HCC). In this study, we identified corosolic acid (CA), which exists in the root of Actinidia chinensis (藤梨), as having a significant anti-cancer effect on HCC cells. We found that CA inhibits VEGFR2 kinase activity by directly interacting with the ATP binding pocket. CA down-regulates the VEGFR2/Src/FAK/cdc42 axis, subsequently decreasing F-actin formation and migratory activity of Huh7 cells in vitro. In an in vivo model, CA exhibites an effective dose (5 mg/kg/day) on tumor growth, and we further demonstrate that CA has a synergistic effect with sorafenib within a wide range of concentrations. In conclusion, we elucidate the effects and molecular mechanism for CA on HCC cells and suggest that CA could serve as a therapeutic or adjuvant target for patients with aggressive HCC.