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.

南泰受体 (RON) 与多种人类恶性肿瘤的细胞增殖、转移和化疗耐药有关。由 RON 转录本编码的短型 RON (sf-RON) 在胃癌组织中过度表达，但其调节功能仍有待阐明。在这里，我们发现sf-RON通过增强葡萄糖代谢来促进胃癌细胞增殖。此外，sf-RON 被证明可通过 AKT1/GSK3β 信号通路诱导 β-catenin 表达水平。同时，在SIX1的启动子区域鉴定出β-catenin的结合位点，也证明β-catenin正向调节SIX1的表达。 SIX1 增强了葡萄糖代谢中关键蛋白的启动子活性，例如 GLUT1 和 LDHA。结果表明，sf-RON通过参与sf-RON/β-catenin/SIX1信号轴调节胃癌细胞增殖和糖代谢，对胃癌治疗靶点的选择具有重要意义。