HPPCn调控HIF-2α促进肝癌细胞的索拉非尼耐药  

HPPCn regulates HIF-2α-promoting sorafenib resistance in hepatoma cells

作　　者：李春男 崔春萍 LI Chun-nan;CUI Chun-ping

机构地区：[1]安徽医科大学,合肥230032 [2]军事医学研究院生命组学研究所国家蛋白质科学中心(北京),北京102206

出　　处：《中国医药生物技术》2018年第3期249-258,共10页Chinese Medicinal Biotechnology

摘　　要：目的确定HPPCn调控低氧诱导因子-2α(HIF-2α)促使肝癌细胞索拉非尼耐药的机制。方法利用实时聚合酶链式反应测定和Western blot印迹检测mR NA及蛋白水平表达。使用MTS测定来确定细胞存活率。细胞transwell和划痕实验被用来检测细胞迁移和侵袭的能力。皮下异种移植小鼠模型模拟肿瘤体内转移。结果缺氧诱导肝癌细胞索拉非尼耐药;HIF-2α参与了缺氧诱导的索拉非尼耐药的发生;HPPCn沉默通过抑制HIF-2α抑制缺氧诱导的索拉非尼耐药。结论持续的索拉非尼治疗产生的抗血管生成效应会引起缺氧,诱导索拉非尼耐药。HPPCn或HIF-2α敲低联合索拉非尼为治疗原发性肝细胞癌提供更有前景的治疗策略。Objective To determine the mechanism of HPPCn promoting sorafenib resistance in hepatocellular carcinoma by accumulating hypoxia inducible factor-2α（HIF-2α）. Methods Real-time polymerase chain reaction and Western blot were used to detect m RNA and protein expression. MTS assays were used to determine cell viability. Cell transwell and scratch assays were used to test cell migration and invasion ability. Subcutaneous xenograft mouse models were used to model tumor metastasis in vivo. Results HIF-2α was involved in hypoxia-mediated sorafenib resistance; HIF-2α silence enhanced inhibition of cell migration of sorafenib under hypoxia in HCC; HPPCn promoted hypoxia-mediated sorafenib resistence by HIF-2α acuumulation; HPPCn sh RNA overcome hypoxia-mediated sorafenib resisitence by inhibiting HIF-2α accumulation in HCC. Conclusions The anti-angiogenic effect of sustained sorafenib treatment induces hypoxia and sorafenib resistance. HPPCn or HIF-2α sh RNA combined with sorafenib provides more promising therapeutic strategies for the treatment of HCC.

关 键 词：癌 肝细胞 缺氧诱导因子-2Α 索拉非尼 肝细胞生成素Cn 

分 类 号：R735.7[医药卫生—肿瘤]