Abstract
Glioma is one of the most common intracranial tumors worldwide, and metastasis and chemoresistance remain a challenge in glioma treatment. This study aims to investigate the effect of sodium valproate on the invasion and metastasis of glioma cells and its mechanism. Glioma cell lines were stimulated with VPA at different concentrations and for different durations of action. U87 glioma cells were transfected with Smad4 plasmid and small interfering RNA, and the changes of EMT-related protein indexes in U87 cells after up- or downregulation of Smad4 were detected by Western blotting. Immunohistochemistry was used to detect the differences in the expression of Smad4, TIF1-γ, and TGF-β proteins in 39 glioma clinical specimens from the Department of Pathology of our hospital. Based on the regulation of EMT-related transcription factors by VPA, our study indicates that VPA inhibits the EMT process of glioma by altering the expression level of Smad4, which is induced by TGF-β1 to form a Smad3/4 complex, thus inducing the EMT process of the tumor and acting as an antitumor target to inhibit the invasive ability of glioma cells. Sodium valproate inhibits glioma invasion and metastasis through the regulation of Smad4 expression.
Highlights
Glioma is one of the most common intracranial tumors worldwide, and metastasis and chemoresistance remain a challenge in glioma treatment [1]
In SHG44, U87, and HEB, Smad4 mRNA and protein levels were significantly higher in U87 cells than in SHG44 cells and normal brain glial cells (HEB), whereas the expression of E-cadherin was lower (Figure 1). is result showed that Smad4 levels were significantly higher in highly invasive cells than in low-invasive cells and normal cells and that there was a potential link between Smad4 protein and cell invasive capacity
When Valproate sodium (VPA) treatment was administered, we found that there was no significant trend in the expression of E-cadherin and N-cadherin in the VPA-treated and control groups (Figure 4(b)), indicating the presence of Smad4 protein. is indicates that the presence of Smad4 protein plays a crucial role in the inhibition of the Epithelial-mesenchymal transition (EMT) process by VPA
Summary
Glioma is one of the most common intracranial tumors worldwide, and metastasis and chemoresistance remain a challenge in glioma treatment [1]. Epithelial-mesenchymal transition (EMT), a pathophysiologic process of conversion of epidermal cells to mesothelial cells in tissues, plays a very important role in the invasion and metastasis of tumors to adjacent and distant tissues and organs [2, 3]. Is process is caused by multiple complexes and growth factors in the tumor microenvironment, and TGF-β is one such factor that has both facilitating and inhibiting roles in the process of tumor invasion and metastasis. Studies have focused on the important role of TGF-β in different stages of tumorigenesis and EMT, but its role in the initial response to EMT remains unclear [4, 5]. Histone acetyltransferases and deacetylases play an important role in the silencing and activation of oncogene expression, along with histone acetylation and deacetylation
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