Original ArticlePseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma

•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.

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.