Dextran Sulfate Effects EMT of Human Gastric Cancer Cells by Reducing HIF-1α/TGF-β

The peritoneal implant metastasis is one of the main pathway and main cause for high mortality for gastric cancer metastasis. Researchs show that epithelial-mesenchymal transition (EMT) playing essential role in modulating gastric cancer metastasis, and the expression of hypoxia inducible factor-1 alpha (HIF-1 alpha) can promote EMT in tumor cells. This research aims to explore the influence and mechanism of Dextran Sulfate (DS) affecting EMT of human gastric cancer. In the present study, we found that DS can enter into the cytoplasm and function in it. Inhibition of HIF-1 alpha or DS significantly inhibit the migration and invasion of human gastric cancer cells, and decrease the mRNA and protein expressions of HIF-1 alpha, matrix metalloproteinase-2 (MMP-2), transforming growth factor-beta (TGF-beta), Twist and N-cadherin (N-cad), rise E-cadherin (E-cad) expression, DS with HIF-1 alpha knockdown has a stronger effect. In vivo studies indicated that compared with using DS or HIF-1 alpha knockdown alone, DS with HIF-1 alpha knockdown can better suppress the volume and number of metastatic tumors, and reduce the mRNA and protein expressions of HIF-1 alpha, MMP-2, TGF-beta, Twist and N-cad in metastatic tumor tissues of nude mice. We further demonstrated that the expression of HIF-1 alpha, MMP-2, TGF-beta, Twist and N-cad were higher in well and poorly differentiated gastric cancer than paracancerous tissue, and poorly differentiated gastric cancer were even higher, while E-cad expression was opposite. Taken together, this study shows that DS can interfere the expression of HIF-1 alpha, thereby inhibiting TGF-beta-mediated EMT of gastric cancer cells, and demonstrated a promising application of DS in gastric cancer therapy.