标题：Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma
作者：Liu, Weijun; Chen, Hanxiang; Wong, Nathan; Haynes, Wesley; Baker, Callie M.; Wang, Xiaowei
作者机构：[Liu, Weijun; Chen, Hanxiang; Wong, Nathan; Haynes, Wesley; Baker, Callie M.; Wang, Xiaowei] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO 更多
通讯作者地址：[Wang, XW]Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO 63108 USA.
关键词：MicroRNA; miR-126; Renal cell carcinoma; Hypoxia; Pseudohypoxia
摘要：Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood. MicroRNA miR-126 has decreased expression in metastatic or relapsed ccRCC as compared to primary tumors, but the mechanisms by which miR-126 is implicated in RCC remain unknown. Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway. Specifically, miR-126 inhibits HIFa protein expression independent of von Hippel-Lindau tumor suppressor (VHL). On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFa expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively. Finally, the clinical relevance of miR-126 modulated gene regulation in ccRCC has been confirmed with profiling data from The Cancer Genome Atlas. (C) 2017 Elsevier B.V. All rights reserved.