Journal Article

Reversal and Prevention of Arsenic-Induced Human Bronchial Epithelial Cell Malignant Transformation by microRNA-200b

Zhishan Wang, Yong Zhao, Eric Smith, Gregory J. Goodall, Paul A. Drew, Thomas Brabletz and Chengfeng Yang

in Toxicological Sciences

Volume 121, issue 1, pages 110-122
Published in print May 2011 | ISSN: 1096-6080
Published online February 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr029
Reversal and Prevention of Arsenic-Induced Human Bronchial Epithelial Cell Malignant Transformation by microRNA-200b

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Arsenic is a well-recognized human carcinogen, yet the mechanism by which it causes human cancer has not been elucidated. MicroRNAs (miRNAs) are a big family of small noncoding RNAs and negatively regulate the expression of a large number of protein-coding genes. We investigated the role of miRNAs in arsenic-induced human bronchial epithelial cell malignant transformation and tumor formation. We found that prolonged exposure of immortalized p53-knocked down human bronchial epithelial cells (p53lowHBECs) to low levels of arsenite (NaAsO2, 2.5 μM) caused malignant transformation that was accompanied by epithelial to mesenchymal transition (EMT) and reduction in the levels of miR-200 family members. Stably reexpressing miR-200b in arsenite-transformed cells (As-p53lowHBECs) completely reversed their transformed phenotypes, as evidenced by inhibition of colony formation in soft agar and prevention of xenograft tumor formation in nude mice. Moreover, stably expressing miR-200b alone in parental nontransformed p53lowHBECs was sufficient to completely prevent arsenite exposure from inducing EMT and malignant transformation. Further mechanistic studies showed that depletion of miR-200 in arsenite-transformed cells involved induction of the EMT-inducing transcription factors zinc-finger E-box-binding homeobox factor 1 (ZEB1) and ZEB2 and increased methylation of miR-200 promoters. Stably expressing ZEB1 alone in parental nontransformed p53lowHBECs was sufficient to deplete miR-200, induce EMT and cause cell transformation, phenocopying the oncogenic effect of 16-week arsenite exposure. These findings establish for the first time a causal role for depletion of miR-200b expression in human cell malignant transformation and tumor formation resulting from arsenic exposure.

Keywords: arsenic; miRNA-200; ZEB; cell transformation; chemical carcinogenesis

Journal Article.  6876 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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