核受体LRH-1参与肝癌细胞对奥沙利铂耐药过程中的分子机制研究

最近研究表明核受体LRH-1参与多种肿瘤的发生。我们的前期研究已经证实LRH-1能够通过上调c-myc、cyclin E1的表达水平，同时抑制p21的表达水平来促进肝癌发生和发展。同时我们发现用奥沙利铂处理HepG2、HuH-7和人肝癌原代培养细胞后，能促进LRH-1的表达升高，同时能促进MDR1基因表达上升，用LRH-1抑制剂ML-180处理细胞后能回复MDR1基因的表达水平；在HepG2和HuH-7中过表达LRH-1后能使细胞对奥沙利铂更耐受，同时过表达LRH-1后能促进MDR1基因的表达水平；用LRH-1特异性小分子抑制剂ML-180处理人肝癌细胞多药耐药株SNU-398后，细胞对奥沙利铂更敏感；基于上述结果，我们推测：LRH-1在肝癌细胞中通过调控MDR1基因的表达，从而促进肝癌细胞对奥沙利铂耐药。本项目旨在证明LRH-1在肝癌细胞对奥沙利铂耐药中的功能，并探索此过程中的分子机制。

Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is proved to play a positive role in several cancers including breast cancer, pancreatic cancer, intestinal cancer and prostate cancer in recent years. Our previous data indicate that LRH-1 drives hepatocellular carcinoma partially through induction of c-myc and cyclin E1, and suppression of p21. Recently, our in vitro results suggest that oxaliplatin treatment could induce the expression of LRH-1 and MDR1, while the LRH-1 specific antagonist ML-180 could reverse the MDR1 expression, in HepG2、HuH-7 and the primary culture cells of HCC. In addition, overexpression of LRH-1 in HepG2 and HuH-7 increase their resistant capacity to oxaliplatin and induce the MDR1 expression level; treatment with LRH-1 specific antagonist ML-180 in SNU-398 decrease its resistant capacity to oxaliplatin. We propose that LRH-1 could promote the oxaliplatin resistance of HCC partially through induction of MDR1 expression.