The Role of Angiopoietin-Like Protein 1 in Sorafenib Resistance and Cancer Stemness of Hepatocellular Carcinoma Cells

Liver cancer is one of the most common cancers, and has high mortality worldwide. About 85% of liver cancer is hepatocellular carcinoma (HCC). Sorafenib is a small molecular inhibitor that targets to several tyrosine kinases and affects multiple cellular functions, including angiogenesis, proliferation, survival and metastasis. Although sorafenib is the standard treatment of advanced hepatocellular carcinoma, but not all of the HCC patients respond to sorafenib treatment and some patients can develop resistance after treatment of sorafenib for a few months. Therefore, it is needed to study the molecular mechanisms of sorafenib resistance in HCC. Recently, angiopoietin-like protein 1 (ANGPTL1), a member of the angiopoietin-like protein family, has been reported as an anti-angiogenic molecule that inhibits proliferation, migration, tube formation, and adhesion of endothelial cells. We also found that ANGPTL1 significantly suppresses the migratory, invasive, and metastatic capabilities of cancer cells through downregulation of the zinc-finger protein Slug (J Clin Invest. 2013; 123(3):1082-95.). Slug also has been reported to be an important transcriptional factor of epithelial-mesenchymal transition involved in metastasis and drug resistance of cancer. Therefore, our goal is to investigate the molecular mechanisms of the ANGPTL1- mediated sorafenib resistance in HCC. The specific aims as following will help us to reveal the goal. SPECIFIC AIM 1: Define the impact of ANGPTL1 on sorafenib resistance and cancer stemness of HCC cells. SPECIFIC AIM 2: Investigate the effects of ANGPTL1-regulated Slug expression in sorafenib resistance and cancer stemness of HCC cells. SPECIFIC AIM 3: Reveal the molecular mechanisms of ANGPTL1-regulated Slug expression in sorafenib resistance and cancer stemness of HCC cells. SPECIFIC AIM 4: Evaluate the biological significance of regulatory molecules, Slug and ANGPTL1 in animal model and HCC patients with sorafenib resistance. Achievements of these specific aims will help us to establish signaling networks to better understand the critical issues of sorafenib resistance. Furthermore, the findings from this project may provide more potential targets to develop novel anti-cancer therapeutic strategies.