Inhibitory Effects And Molecular Mechanisms Research Of As₄S₄ On Gastric Cancer Invasion And Metastasis

[Objectives] To investigate themolecular mechanisms about inhibitory effects of As₄S₄ on gastric cancer invasion and metastasis, and enrich the theoretical basis of arsenic sulfide on gastric cancer individualized treatment, which will provide a scientific basis for its clinical application. [Methods] The human gastric AGS, MGC803 cell lines were selected as our experimental material.Wound healing migration assay, Transwell invasion assay were carried out to determine the effects of As₄S₄ on cell migration and invasion. To determine the possible mechanisms in this process, the protein levels of E-cadherin??-catenin?Sp1?KLF4?VEGF were measured by Western blotting analysis.The activity of MMP-2 and MMP-9 in MGC803 cells was demonstratedby Zymography assay.Mouse xenograft models were established by inoculation with MGC803 cells. Intraperitoneal injected arsenic sulfide for 3 weeks, monitored nude body weight and tumor diameter changes, then the inhibition rate was calculated, and the morphology and proportion of apoptotic cells in tumor tissues were detected byHE staining and TUN EL assay, respectively.What's more, the changes of tumor invasion and metastasis associated protein and gene in tissues were measured by immunohistochemistry, Western blotting and RT-PCR method. [Results] Would healing assay and Transwell assay demonstrated that As₄S₄ could inhibite the invasion and migration of gastric cancer AGS and MGC803 cellssignificantly. Western blotting showed thatAs₄S₄ up-ragulated the expressio n of E-cadherin and KLF4 while down-regulated the expression of Sp1 and VEGF. Moreover, the proteolytic activity rather than the expression of matrix metalloproteinase?MMP?-2, MMP-9 were suppressed by As₄S₄ in MGC803 cells. Using xenograft as a model, we showed that As₄S₄ suppressed the ability of tumor growth and invasion effectly. HE and TUNEL assay showed that the apoptotic cells and inflammatory cells in As₄S₄ treatment group were increased. Immunohistochemistry, Western blotting and RT-PCR results suggest that As₄S₄ inhibit tumor invasion and metastasis may be related to the upregulated of E-cadherin protein level,and the downregulatedof ?-catenin, Sp1, VEGF and CD34 expression level. Theseresultwere consistent with what we detected in vitro. [Conclusions] These results reveal that As₄S₄ might inhibit the invasion and metastasis of gastric cancer through multiple avenues, and the mian mechanism might by regulating MMP2/E-cad through increased the expression their upstream target KLF4. Besides, the effects probably were associated with the inhibition of angiogenesis. Our data suggest that As₄S₄ is a potential agent for clinical use in preventing gastric cancer invasion and metastasis.