Role of Klotho in Cell Proliferation in Human Hepatocellular Carcinoma

• Main Authors: Lin,Hui-Chi, 林慧绮
• Other Authors: Huang,Jau-Shyang
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/34140995887387746159

碩士 === 中華醫事科技大學 === 生物科技系暨生物醫學研究所 === 103 === Klotho was originally characterized as an aging suppressor gene that predisposed klotho-deficient mice to premature aging-like syndrome. Although klotho was recently reported to exhibit tumor suppressive properties during various malignant transformations, the functional role and molecular mechanism of klotho in hepatocarcinogenesis remains poorly understood. In the present study, we examined the role of klotho in cell proliferation in human hepatocellular carcinoma. We showed that there is no difference between normal HSC and cancerous HepG2 cells in klotho protein expression. Treatment of HepG2 cells with exogenous klotho protein for 3 days resulted in dose-dependent increase of proliferation. Specific JNK inhibitor SP600125, p38 MAPK inhibitor SB203580, and ERK inhibitor PD98059 significantly prevented klotho-induced cell growth. Moreover, antioxidants N-acetylcysteine (NAC) and taurine significantly reversed klotho-enhanced the protein synthesis of klotho. Both these antioxidants suppress klotho-induced proliferation of HepG2 cells through inactivation of the ERK/p38 MAPK pathway. On the other hand, the ability of klotho to induce cell cycle progression was verified by the observation that it significantly decreased the protein levels of p27Kip1 and p21Wafl/Cip1. Taurine blocked klotho-accelerated cell cycle progression maybe through induction of p27Kip1 and p21Waf1/Cip1. It was also found that NAC and taurine did not enhance the activity of caspase-3. We suggest that inhibition of klotho expression is required for NAC/taurine-induced cell cycle arrest but not NAC/taurine-modulated apoptosis in HepG2 cells.