Upregulation of microRNA-4417 and Its Target Genes Contribute to Nickel Chloride-promoted Lung Epithelial Cell Fibrogenesis and Tumorigenesis

Chih-Hsien Wu,Ming-Fang Wu,Chih-Yi Chen,Tsui-Chun Tsou,Kun-Tu Yeh,Jiunn-Liang Ko,Yi-Min Hsiao

doi:10.1038/s41598-017-14610-7

Abstract

Nickel compounds have been classified as carcinogens and shown to be associated with induction of epithelial-mesenchymal transition (EMT) in fibrogenesis and tumorigenesis, as well as the crucial role of microRNAs (miRNAs) and their related genes in controlling EMT and cancer metastasis. Thus, the mechanisms involved in the regulation of EMT in nickel-treated cells are of potential interest in understanding lung fibrosis and tumor progression. We investigated the miRNA-dependent mechanisms involved in nickel-induced EMT in lung epithelial cells. Nickel increased miR-4417 expression and decreased its target gene TAB2 expression. Treatment of cells with TGF-β inhibitor SB525334 significantly blocked NiCl2 and TGF-β-induced EMT. The expression of miR-4417 was abolished by SB525334 in TGF-β-treated cells, but not in nickel-treated cells. Both overexpression of miR-4417 and silencing of TAB2 induced fibronectin expression, but did not reduce E-cadherin expression. Moreover, oral administration of nickel promoted lung tumor growth in nude mice that had received BEAS-2B transformed cells by intravenous injection. The induction of EMT by nickel is mediated through multiple pathways. Induction of abundant miR-4417 and reduction of TAB2 expression following nickel exposure and may be involved in nickel-induced fibronectin. These findings provide novel insight into the roles of nickel in fibrogenesis and tumor progression.

Highlights

MiRNAs negatively regulate the stability and translation of target messenger RNAs at the 3′-untranslated region (3′UTR)[3]
To better understand the role of nickel compounds in tumor progression, we further explored the mechanism of tumorigenesis in immortalized human bronchial epithelial cell line (BEAS-2B cells) and lung cancer cell line (A549 cells)
To investigate whether NiCl2 induces epithelial-mesenchymal transition (EMT) in lung carcinogenesis and fibrosis via TGF-β signaling pathway, we analyzed the effects of SB525334, a potent and selective inhibitor of the TGF-β receptor, on E-cadherin and fibronectin expressions in BEAS-2B and A549 cells

Summary

Introduction

MiRNAs negatively regulate the stability and translation of target messenger RNAs (mRNAs) at the 3′-untranslated region (3′UTR)[3] They have been reported to regulate the expression of >60% of human protein-coding genes[4] and to be found in abundance in many human cell types[5]. MiR-222 promoted cell proliferation during nickel-induced tumorigenesis in part by regulating the expression levels of its target genes, CDKN1B and CDKN1C8. EMT is a process by which the epithelial cells convert to a mesenchymal state that involves normal embryological development and an increase in fibroid morphology. It is implicated in various adult pathologies including cancer aggressiveness and metastasis[10]. Mesenchymal markers are fundamentally important to epigenetic regulation, but have not yet been studied in tumorigenesis

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