Reversal and prevention of arsenic-induced human bronchial epithelial cell malignant transformation by microRNA-200b

摘要: Arsenic is a well-recognized human carcinogen, yet the mechanism by which it causes cancer has not been elucidated. MicroRNAs (miRNAs) are big family of small noncoding RNAs and negatively regulate expression large number protein-coding genes. We investigated role miRNAs in arsenic-induced bronchial epithelial cell malignant transformation tumor formation. found that prolonged exposure immortalized p53-knocked down cells (p53(low)HBECs) to low levels arsenite (NaAsO₂, 2.5 μM) caused was accompanied mesenchymal transition (EMT) reduction miR-200 members. Stably reexpressing miR-200b arsenite-transformed (As-p53(low)HBECs) completely reversed their transformed phenotypes, as evidenced inhibition colony formation soft agar prevention xenograft nude mice. Moreover, stably expressing alone parental nontransformed p53(low)HBECs sufficient prevent from inducing EMT transformation. Further mechanistic studies showed depletion involved induction EMT-inducing transcription factors zinc-finger E-box-binding homeobox factor 1 (ZEB1) ZEB2 increased methylation promoters. ZEB1 deplete miR-200, induce cause transformation, phenocopying oncogenic effect 16-week exposure. These findings establish for first time causal resulting arsenic