Valproic acid inhibits epithelial-mesenchymal transition in Renal cell carcinoma by decreasing SMAD4 expression

Abstract

Renal cell carcinoma (RCC) is the most common malignancy in urogenital neoplasms worldwide. According to previous studies, valproic acid (VPA), an anticonvulsant drug, can suppress tumor metastasis and decrease the expression level of Mothers against decapentaplegic homolog 4 (SMAD4) and therefore may inhibit epithelial-mesenchymal transition (EMT), which is responsible for cancer metastasis. However, the association between VPA, EMT and SMAD4 in RCC metastasis remains obscure. In the present study, it was demonstrated that in the RCC cell lines 786-O and Caki-1 treated with VPA, the neural (N)-cadherin, vimentin and SMAD4 protein and mRNA levels were decreased, accompanied with an increase in expression of epithelial (E)-cadherin. Silencing SMAD4 expression decreased the expression of EMT markers, including N-cadherin and simultaneously upregulated E-cadherin in RCC cell lines. SMAD4 overexpression counteracted the VPA-mediated EMT-inhibitory effect (P<0.05). The present study demonstrates that VPA inhibited EMT in RCC cells via altering SMAD4 expression. In addition, immunohistochemical staining demonstrated that transforming growth factor-β (TGF-β) and low expression of SMAD4 was associated with a lower Fuhrman grade and low expression of transcription intermediary factor 1-γ was associated with a higher tumor Fuhrman grade (P<0.05), Therefore, based on the regulatory effect of SMAD4 on EMT-associated transcription factors, SMAD4 which can form a SMAD3/SMAD4 complex induced by TGF-β, could be a potential anticancer drug target inhibiting tumor invasion and metastasis in RCC.