title: Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma.
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.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Weijun
authors.initials: W
authors.lastname: Liu
authors.affiliation: Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Hanxiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Wong
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Wesley
authors.initials: W
authors.lastname: Haynes
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Callie M
authors.initials: CM
authors.lastname: Baker
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: xiaowei.wang@wustl.edu.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D064113:CRISPR-Cas Systems; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D019295:Computational Biology; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000072258:Tumor Hypoxia; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D002945:Cisplatin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D027283:Large Neutral Amino Acid-Transporter 1; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; D058570:TOR Serine-Threonine Kinases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C527111:MIRN126 microRNA, human; C051321:SERPINE1 protein, human; C546842:MTOR protein, human; C497446:VHL protein, human
keywords: Hypoxia; MicroRNA; Pseudohypoxia; Renal cell carcinoma; miR-126