Serine/threonine-protein kinase 24 is an inhibitor of gastric cancer metastasis

Abstract Background: Gastric cancer patients often present with distant metastasis and advanced stages. Suppressing serine/threonine-protein kinase 24 (STK24, also known as MST3) is known to promote gastric tumorigenesis. Here, we investigated the association between STK24 and the metastasis of gastric cancer.Methods: CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technology was used for genetic knockout of STK24 at the genomic DNA level in human MKN45 and mouse M12 gastric cancer cells. To assess the effects of STK24 knockdown, western blot, cell migration, and wound healing assays were conducted in vitro. An in vivo mouse model of liver metastasis was established and tested, and bioinformatics analyses were performed.Results: The knockdown of the STK24 gene enhanced cell migration and increased liver metastasis in the mouse model of gastric cancer. STK24-silenced tumors suppressed CD4+ T cells and induced the expansion of CD11b+Ly6C+ myeloid-derived suppressor cells and F4/80+ macrophages in the spleen of the mice. In MKN45 cells, STK24 silencing resulted in downregulation of E-cadherin (CDH1, Cadherin-1, or epithelial cadherin). In 38 matched specimens of gastric adenocarcinomas and normal tissues, we examined STK24 and CDH1 expression levels via western blot; a significant positive correlation was found between the expression levels of STK24 and CDH1 (R2 = 0.5507, P = 9.72 × 10−8). Furthermore, in Oncomine database and Kaplan-Meier plotter analysis, the loss of CDH1, increase in CCL2, and upregulation of CD44 were correlated with poor prognosis in gastric cancer patients.Conclusions: Our results demonstrate that knockdown of STK24 increases cell migration and metastasis. STK24 suppression is also positively correlated with CDH1 expression in gastric cancer metastasis. Having developed an experimental metastatic model of gastric cancer in syngeneic inbred mice, we have shown that STK24 is important for immune regulation and regulates CDH1 expression during gastric metastasis.