MicroRNA-130a targeting hypoxia-inducible factor 1 alpha suppresses cell metastasis and Warburg effect of NSCLC cells under hypoxia

Abstract

MicroRNAs have been demonstrated to play critical role in the development of non-small cell lung cancer (NSCLC) and hypoxia is a common hallmark of NSCLC. MiRNA-130a-3p (miR-130a) is a well-known tumor suppressor, and we intended to explore the role and mechanism of miR-130a in NSCLC cells under hypoxia. We used real-time quantitative polymerase chain reaction method to measure miR-130a expression, and found that miR-130a was downregulated in human NSCLC tumors and cell lines (A549 and H1299), accompanied with upregulation of hypoxia-inducible factor 1 alpha (HIF1A), a marker of hypoxia. Besides, miR-130a low expression was associated with tumor burden and poor overall survival. Moreover, miR-130a expression was even downregulated in hypoxia-treated A549 and H1299 cells. Ectopic expression of miR-130a suppressed Warburg effect, migration and invasion in hypoxic A549 and H1299 cells, as evidenced by decreased glucose consumption, lactate production, hexokinase 2 expression, and numbers of migration cells and invasion cells analyzed by commercial glucose and lactate assay kits, western blotting and transwell assays. Furthermore, overexpression of miR-130a restrained xenograft tumor growth of A549 cells in mice. However, recovery of HIF1A could reverse the suppressive effect of miR-130a overexpression on cell migration, invasion and Warburg effect in hypoxic A549 and H1299 cells. Mechanically, dual-luciferase reporter assay, RNA immunoprecipitation and RNA pull-down assay confirmed a target relationship between miR-130a and HIF1A. Collectively, we demonstrated an anti-tumor role of miR-130a in NSCLC cells under hypoxia through targeting HIF1A, suggesting a potential target for the interfering of NSCLC.