RON and RONΔ160 promote gastric cancer cell proliferation, migration, and adaption to hypoxia via interaction with β-catenin

Aberrant accumulation of the receptor tyrosine kinase recepteur d'origine nantais (RON) has been verified in gastric adenocarcinoma. Upregulation of RON and its splice variant RON Delta 160 contribute to the growth and migration in gastric cancer cells in vitro. However, the mechanisms of RON/RON Delta 160-mediated gastric cancer growth and metastasis remain vague. We therefore examined the actions of RON, RON Delta 160, and beta-catenin in gastric cancer cells and tissue samples, and their effects on cell growth in vitro and in vivo. We found that in gastric cancer samples and cell lines, there was positive correlation between RON/RON Delta 160 and beta-catenin levels, and that they formed a RON/RON Delta 160-beta-catenin complex which was translocated to the nucleus. Hypoxia led the binding of hypoxia-inducible factor-1 alpha to the RON/RON Delta 160-beta-catenin complex, which increased nuclear translocation and expression of downstream oncogenic signaling molecules. Overexpression of RON/RON Delta 160 promoted the proliferation and migration of gastric cancer cells, which were also enhanced by hypoxia. Suppression of RON using siRNA or anti-RON monoclonal antibody diminished gastric cancer cell and tumor growth in vitro and in vivo. These findings establish a link between the receptor tyrosine kinase RON and beta-catenin and provide insight into the mechanism by which they contribute to gastric cancer progression.