Nickel-induced epithelial-mesenchymal transition by reactive oxygen species generation and E-cadherin promoter hypermethylation.
Epithelial-mesenchymal transition (EMT) is considered a critical event in the pathogenesis of lung fibrosis and tumor metastasis. During EMT, the expression of differentiation markers switches from cell-cell junction proteins such as E-cadherin to mesenchymal markers such as fibronectin. Although nickel-containing compounds have been shown to be associated with lung carcinogenesis, the role of nickel in the EMT process in bronchial epithelial cells is not clear. The aim of this study was to examine whether nickel contributes to EMT in human bronchial epithelial cells. We also attempted to clarify the mechanisms involved in NiCl(2)-induced EMT. Our results showed that NiCl(2) induced EMT phenotype marker alterations such as up-regulation of fibronectin and down-regulation of E-cadherin. In addition, the potent antioxidant N-acetylcysteine blocked EMT and expression of HIF-1α induced by NiCl(2), whereas the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored the down-regulation of E-cadherin induced by NiCl(2). Promoter hypermethylation of E-cadherin, determined by quantitative real time methyl-specific PCR and bisulfate sequencing, was also induced by NiCl(2). These results shed new light on the contribution of NiCl(2) to carcinogenesis. Specifically, NiCl(2) induces down-regulation of E-cadherin by reactive oxygen species generation and promoter hypermethylation. This study demonstrates for the first time that nickel induces EMT in bronchial epithelial cells.
Institute of Medicine, Chung Shan Medical University, Chung Shan Medical University Hospital, Taichung 40203, Taiwan.
Chih-Hsien
CH
Wu
Sheau-Chung
SC
Tang
Po-Hui
PH
Wang
Huei
H
Lee
Jiunn-Liang
JL
Ko
D000111:Acetylcysteine / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002461:Cell Line, Transformed; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D007365:Intercellular Junctions / Q000235:genetics / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
D000943:Antigens, Differentiation; D015820:Cadherins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D016166:Free Radical Scavengers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C022838:nickel chloride; D000077209:Decitabine; D009532:Nickel; D015254:DNA Modification Methylases; D001374:Azacitidine; D000111:Acetylcysteine