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Vasohibin-2 is required for epithelial-mesenchymal transition of ovarian cancer cells by modulating transforming growth factor-β signaling

2017; Wiley; Volume: 108; Issue: 3 Linguagem: Inglês

10.1111/cas.13157

1349-7006

Rie Iida‐Norita, Yasuhiro Suzuki, Yutaka Furutani, Kazuki Takahashi, Yasuhiro Yoshimatsu, Katarzyna A. Podyma‐Inoue, Tetsuro Watabe, Yasufumi Sato,

Hedgehog Signaling Pathway Studies

Vasohibin‐2 ( VASH 2) is a homolog of VASH 1, an endothelium‐derived angiogenesis inhibitor. Vasohibin‐2 is mainly expressed in cancer cells, and has been implicated in the progression of cancer by inducing angiogenesis and tumor growth. Although VASH 2 has been recently reported to be involved in epithelial–mesenchymal transition ( EMT ), its precise roles are obscure. The aim of the present study was to clarify the role of VASH 2 in the EMT of cancer cells in relation to transforming growth factor‐β ( TGF ‐β) signaling, which is a major stimulator of EMT . Decreased expression of VASH 2 in ovarian cancer cells significantly repressed the expression of TGF ‐β type I receptor, namely activin receptor‐like kinase 5. Transforming growth factor‐β1‐induced phosphorylation of Smad2 and Smad3 was markedly decreased in VASH 2 knockdown cells while the expression of Smad2 and Smad3 was unchanged. Accordingly, the responses to TGF ‐β1 shown by promoter assay and plasminogen activator inhibitor type 1 expression were significantly attenuated in VASH 2 knockdown cells. Furthermore, knockdown of VASH 2 in cancer cells abrogated the TGF ‐β1‐induced reduced expression of epithelial markers including E‐cadherin, and the elevated expression of mesenchymal markers including fibronectin, ZEB 2, and Snail2, suggesting that endogenous VASH 2 is required for TGF ‐β1‐induced EMT . In accordance with these results, the effects of TGF ‐β1 on cell morphology, migration, invasion, and MMP 2 expression were also abrogated when VASH 2 was knocked down. These results indicate that VASH 2 played a significant role in the EMT by modulating the TGF ‐β signaling. We propose that VASH 2 would be a novel molecular target for the prevention of EMT in cancers.