Research Paper Volume 11, Issue 9 pp 2735—2748

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

Donghui Zhou 1, , Ling Huang 1, , Yong Zhou 1, , Tao Wei 1, , Lina Yang 2, , Chao Li 3, ,

  • 1 Department of Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
  • 2 Department of Oncology, the Affiliated Dongnan Hospital of Xiamen University, Zhangzhou, Fujian, 363000, China
  • 3 Department of Medical Oncology, Affiliated Hospital of Inner Mongolia Medical University, Huhhot, Inner Mongolia, 010030, China

received: January 25, 2019 ; accepted: April 27, 2019 ; published: May 13, 2019 ;

https://doi.org/10.18632/aging.101945
How to Cite

Copyright: Zhou et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

RON: recepteur d’origine nantais; RTKS: receptor tyrosine kinases; PI3K: phosphatidylinostiol-3 kinase; HIF-1α: hypoxia-inducible factor-1α.