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.