Abstract
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 RONΔ160 contribute to the growth and migration in gastric cancer cells in vitro. However, the mechanisms of RON/RONΔ160-mediated gastric cancer growth and metastasis remain vague. We therefore examined the actions of RON, RONΔ160, and β-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/RONΔ160 and β-catenin levels, and that they formed a RON/RONΔ160-β-catenin complex which was translocated to the nucleus. Hypoxia led the binding of hypoxia-inducible factor-1α to the RON/RONΔ160-β-catenin complex, which increased nuclear translocation and expression of downstream oncogenic signaling molecules. Overexpression of RON/RONΔ160 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 β-catenin and provide insight into the mechanism by which they contribute to gastric cancer progression.
Highlights
Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors that participate in various signaling pathways regulating cellular proliferation, survival, apoptosis, and migration [1, 2]
By immunoblotting 30 samples of gastric cancer tissue, adjacent paracancerous tissues, and normal gastric tissues, we found that expression of Recepteur d'Origine Nantais (RON) and RONΔ160 is positively associated with the level β-catenin protein in gastric cancer samples but not paracancerous or normal tissues (Figure 1A)
These results show that there is a link between RON/RONΔ160 and β-catenin in gastric cancer tissues, and that β-catenin may be a key regulator of RON signaling during the pathogenesis of gastric cancer
Summary
Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors that participate in various signaling pathways regulating cellular proliferation, survival, apoptosis, and migration [1, 2]. RON and www.aging-us.com its splice variants exhibit prominent effects on the occurrence, progression, and metastasis of rectal cancer [15]. Expression of RON and RONΔ165 is significantly up-regulated in the gastric cancer tissue [16]. The truncation of RON to produce RONΔ160 leads to structural changes in the protein that enhances human colorectal adenocarcinomas cells growth in vitro and in vivo [17, 18]. Forced expression of RONΔ160 effectively enhances the growth and migration of gastric cells in vitro and in vivo [19]. We hypothesize that RON and RONΔ160 contribute to the pathogenesis of gastric cancer and have an essential stimulatory effect on the proliferation and metastasis of gastric cancer cells
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