Mucin 17 inhibits the progression of human gastric cancer by limiting inflammatory responses through a MYH9-p53-RhoA regulatory feedback loop.

ABSTRACT: BACKGROUND:Mucins are key components of the mucosal barrier in the stomach that protects epithelia from carcinogenic effects of chronic inflammation. Analysis of The Cancer Genome Atlas database indicated that mucin-17 (MUC17) was more highly expressed in gastric cancer (GC) specimens, with favourable prognosis for patients. To explore the underlying mechanisms, we investigated the potential role of MUC17 in controlling chronic gastric inflammation. METHODS:We initially quantified the expression of MUC17 and inflammatory factor, as well as the association of MUC17 with survive in GC using immunohistochemistry. To establish how the inflammatory factors affect MUC17 expression, we explored luciferase reporter, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift (EMSA) assays. The role and mechanism that MUC17 plays in inflammation-induced cell proliferation was examined in AGS cells with reduced MUC17 expression and MKN45 cells overexpressing a truncated MUC17. RESULTS:We found MUC17 was induced by inflammatory cytokines in GC cells via CDX1upregulation. MUC17 thus inactivated NF?B to inhibit GC cell proliferation in response to pro-inflammatory cytokines. We also revealed that the function of MUC17 was dependent on its conserved epidermal growth factor domain and on downstream sequences to enable its interaction with myosin-9, resulting in a sustained regulatory feedback loop between myosin-9, p53, and RhoA, and then activation of p38 to negatively regulate the NF?B pathway in GC cells. This mechanism was also confirmed in vivo. CONCLUSIONS:Our study demonstrates MUC17 as a GC suppressor protein which has the therapeutic potential for human GC.

SUBMITTER: Yang B 

PROVIDER: S-EPMC6604468 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature