Characterization of CRKL as a therapeutic target in sorafenib resistant hepatocellular carcinoma

• Main Authors: Chia-Fen Chang, 張佳棻
• Other Authors: Chi-Ying F. Huang
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/69356024768731054951

碩士 === 國立陽明大學 === 生物藥學研究所 === 102 === Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and frequently resistant to systemic therapies and recurs even after aggressive local therapies. Currently, only sorafenib, which prolongs patient’s survival for 2-3 months, has been approved by the FDA for HCC treatment. Therefore, the biomarker(s) to analyze the probability of the recurrence and sorafenib response of HCC patients is an urgently unmet medical need. We have recently identified CRKL as a newly prognosis factor of HCC. However, the role of CRKL in HCC is still unknown. In this study, I aimed to characterize the mechanism of CRKL related to sorafenib resistance of HCC. The results of micro-western and immunoblotting showed that CRKL may be involved in AKT, ERK, and p70 S6 kinase in HCC. Moreover, sorafenib-resistant Huh7 cell (Huh7R cells) exhibited highly migratory ability coupled with mesenchymal characteristics via activated CRKL, AKT, ERK and NF-κB signaling. Knockdown of CRKL increased cell viability and suppressed Snail in epithelial-mesenchymal transition (EMT) process of HCC. Furthermore, overexpression of CRKL increased cell migratory ability via Snail in EMT process to reverse sorafenib response. Taken together, CRKL might be a therapeutic target for predictive marker of sorafenib for HCC treatment.