Short-form RON (sf-RON) enhances glucose metabolism to promote cell proliferation via activating β-catenin/SIX1 signaling pathway in gastric cancer
Ziliang Wang, Yufei Yang, Shuang Hu, Jian He, Zheng Wu, Zihao Qi, Mingzhu Huang, Rujiao Liu, Ying Lin, Cong Tan, Midie Xu, Zhe Zhang
Abstract
Recepteur d'origine nantais (RON) has been implicated in cell proliferation, metastasis, and chemoresistance of various human malignancies. The short-form RON (sf-RON) encoded by RON transcripts was overexpressed in gastric cancer tissues, but its regulatory functions remain illustrated. Here, we found that sf-RON promoted gastric cancer cell proliferation by enhancing glucose metabolism. Furthermore, sf-RON was proved to induce the β-catenin expression level through the AKT1/GSK3β signaling pathway. Meanwhile, the binding sites of β-catenin were identified in the promoter region of SIX1 and it was also demonstrated that β-catenin positively regulated SIX1 expression. SIX1 enhanced the promoter activity of key proteins in glucose metabolism, such as GLUT1 and LDHA. Results indicated that sf-RON regulated the cell proliferation and glucose metabolism of gastric cancer by participating in a sf-RON/β-catenin/SIX1 signaling axis and had significant implications for choosing the therapeutic target of gastric cancer.