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

Abstract

Vasohibin-2 (VASH2) is a homologue of VASH1, an endothelium-derived angiogenesis inhibitor. VASH2 is mainly expressed in cancer cells, and has been implicated in the progression of cancer by inducing angiogenesis and tumor growth. While VASH2 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 VASH2 in the EMT of cancer cells in relation to TGF-β signaling, which is a major stimulator of the EMT. Decreased expression of VASH2 in ovarian cancer cells significantly repressed the expression of TGF-β type I receptor (TβRI), namely ALK5. TGF-β1-induced phosphorylation of Smad2 and Smad3 was markedly decreased in VASH2 knockdown cells while the expression of Smad2 and Smad3 was unchanged. Accordingly, the responses to TGF-β1 shown by promoter assay and PAI-1 expression were significantly attenuated in VASH2 knockdown cells. Furthermore, knockdown of VASH2 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, ZEB2 and Snail2, suggesting that endogenous VASH2 is required for TGF-β1-induced EMT. In accordance with these results, the effects of TGF-β1 on cell morphology, migration, invasion and MMP2 expression were also abrogated when VASH2 was knocked-down. These results indicate that VASH2 played a significant role in the EMT by modulating the TGF-β signaling. We propose that VASH2 would be a novel molecular target for the prevention of the EMT in cancers.

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