截短型RON受体酪氨酸激酶在胃癌转移中的驱动作用机制研究

The RON receptor tyrosine kinase is essential for the tumorigenesis and malignant progression of different types of cancers. As seen in recently evidence, short form RON (sf-RON) is proved to have characteristics of driver alteration. However, the potential role of sf-RON in promoting gastric cancer metastasis remains a poorly defined problem. According to our previous data, sf-RON, rather than full length RON (fl-RON), was constitutively auto-activated irrespective of the ligand Macrophage-stimulating protein (MSP) and c-MET receptor. sf-RON overexpression facilitated cell motility and epithelial-to-mesenchymal transition (EMT)–like process in vitro and increased pulmonary metastatic nodules in xenograft models. Further Whole Genome Expression profile and Gene Ontology analysis indicated this could be associated with upregulation of a serials of growth factors and chemokines related to metastasis. The aim of this study is to elucidate the molecular signaling underlying sf-RON-mediated metastasis in gastric cancer and to demonstrate its potential as a therapeutic target.

RON受体酪氨酸激酶在肿瘤的发生、发展过程中发挥重要作用。最近的研究提示，截短型RON（sf-RON）具有癌症驱动基因的特征，但sf-RON在胃癌中促进转移的分子机制尚不明确。本课题组前期研究发现，截短型sf-RON与野生型完整型RON（fl-RON）不同，它的自发磷酸化过程不依赖巨噬细胞刺激蛋白（MSP）配体，且不受c-MET受体的调控。体外和体内实验证实，sf-RON过表达能够促进胃癌的迁移和转移，诱发EMT样生物学进程。表达谱基因芯片结果进一步提示，这可能与一系列转移相关的生长因子、酶和趋化因子的表达上调有关。本课题拟进一步探讨sf-RON在胃癌转移中的驱动作用的信号转导分子机制，为胃癌分子靶向治疗提供新的靶点和理论依据。

RON已涉及细胞增殖，转移和各种人类恶性肿瘤的化疗耐药性。RON转录本编码的短形式RON (sf-RON)在胃癌组织中过表达，但其调控功能仍不明确。在本研究中，我们发现sf-RON通过促进葡萄糖代谢促进胃癌细胞增殖。进一步证实sfRON可通过AKT1/GSK3β信号通路诱导β-catenin的表达水平。同时，在SIX1的启动子区域发现了β-catenin的结合位点，也证实了β-catenin正向调控SIX1的表达。SIX1增强了葡萄糖代谢关键蛋白GLUT1和LDHA的启动子活性。结果表明，sf-RON通过参与sf-RON/β-catenin/SIX1信号轴调控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。