Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma. (28th May 2017)

• Record Type: Journal Article
• Authors: Liu, Weijun; Chen, Hanxiang; Wong, Nathan; Haynes, Wesley; Baker, Callie M.; Wang, Xiaowei
• Is Part Of: Cancer letters. Volume 394(2017)
• Page Start: 65
• Page End: 75
• Publication Date: 2017-05-28
• Subjects: MicroRNA -- miR-126 -- Renal cell carcinoma -- Hypoxia -- Pseudohypoxia; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.02.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 HIFα 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 HIFα 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. Highlights: By targeting SLC7A5 and SERPINE1, miR-126 plays a major role in regulation of the mTOR/HIF pathway in ccRCC. Dysregulated mTOR/HIF caused by miR-126 deactivation induces pseudohypoxia in ccRCC. Pseudohypoxia caused by miR-126 deactivation leads to therapeutic resistance and increased tumor cell motility in ccRCC. Low miR-126 expression is significantly associated with overall survival and metastasis in ccRCC.