AB66. Gastric mucosa barrier protein MUC17 defenses inflammation factors via Rho/Rock pathway

Background and aims: The damage of gastric mucosa barrier is the initial factor of gastric cancer formation and inflammation is the inducer of gastric cancer development. Our previous genomics study indicated that most of mutant genes involved in inflammation signaling pathway and most of high frequency mutated genes are belonged to MUCIN family, which is the component part of gastric mucosal barrier. More importantly, the survival analysis showed that mutated Mucin 17 (MUC17) benefits overall survival of gastric cancer patients. A systematic study that combined multiple approaches was initiated to define the molecular mechanism of MUC17 in gastric cancer cells.

Methods: Immunohistochemistry and RT-PCR were used to detect the expression level of MUC17 in gastric cancer tissues and cell lines. The activity of the promoter was evaluated by luciferase assay. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation were employed to confirm the interaction between the promoter and its transcriptional factor. MTT assay and flow cytometry were used to detect the effect of MUC17 on cell growth and cell cycle regulation. The protein interaction was identified by immunoprecipitation and mass spectrometer (MS).

Results: cdx1 was identified as the transcriptional factor of MUC17. Inflammation factors led to gene mutation and accumulate mutant MUC17 through upregulating cdx1 in gastric cancer tissues. The conserved EGF-like domain of MUC17 defensed the function of inflammation factors and led to cell differentiation and senescence in gastric cancer. Furthormore, EGF-like domain of MUC17 activated Rho/Rock pathway through interacting MYH9, and then inhibited NFκB pathway, which stimulated by inflammation factors.

Conclusions: Inflammation led to accumulate mutant MUC17 in gastric cancer tissues, and then the conserved EGF-like domain defended the function of inflammation factors and led to cell differentiation and senescence, hence, the patients carried mutated MUC17 have a better prognosis than the patients carried wild type MUC17. This systematic study may offer a new strategy for gastric cancer therapy and a new study direction of the relation between gene mutation and tumor formation.

Keywords: Gastric cancer; gastric mucosal barrier; inflammation; MUC17; mutation