表观遗传沉默的新的抑癌基因ROR2参与上皮-间质转化的分子机理和功能研究

中文摘要

英文摘要

Dysregulation of receptor tyrosine kinase (RTK) has been found in a wide range of cancers, which has been shown to correlate with the development and progression of mutliple cancers. Thus, RTK has become an attractive therapeutic target. We previously have identified a novel methylated gene ROR2 (receptor tyrosine kinase-like orphan receptor 2) using methylation-sensitive representational difference analysis (MS-RDA). ROR2 has been reported to possess dual roles as a tumor suppressor or activator depending on tumor type, while its tumor suppressive function is largely unclear. This proposed proposal aims to explore the tumor suppressive functions of ROR2, its functional relationship with WNT5A, the effect on epithelial mesenchymal transition (EMT) and disrupted cell signaling, as well as its potential as early tumor marker. Through the proposed study, the TSG profile of RTK will be dispersed, and the understanding of tumor suppressive function of RTK family members will be widened, which will highlight the importance of epigenetic alteration in tumorigenesis and develop potent tumor markers for early detection, diagnosis and prevention.

结题摘要

受体酪氨酸激酶介导的信号转导与肿瘤发生发展直接相关，针对该靶点的药物研发已成为当前抗肿瘤治疗的热点，并且取得了重要进展。我们在前期的研究工作中采用甲基化敏感性代表性差异分析法筛选出受体酪氨酸激酶样孤核受体2 (ROR2)基因。根据肿瘤类型的不同ROR2 可发挥肿瘤抑制或激活的双重功能，但其抑癌功能报道甚少。本项目在此基础上，拟全面阐明ROR2 作为新的抑癌基因的生物学功能、与WNT5A 的相关性及参与上皮-间质转化的分子机理和生物学功能，及其甲基化作为肿瘤早期诊断、预防的分子标志物研究。我们的研究发现，ROR2受启动子甲基化调控沉默或低表达于多种常见肿瘤中，包括鼻咽癌，食管癌，但ROR2和WNT5A的表达并无直接的相关性。我们进一步的研究发现，ROR2可通过抑制肿瘤细胞生长，诱导细胞周期抑制和凋亡从而参与肿瘤的抑制，这些效应不依赖于WNT5A的表达。ROR2可通过抑制β-catenin和AKT信号通路，阻滞上皮间质转化和肿瘤的干细胞化，进一步抑制肿瘤细胞侵袭、转移和增加化疗的敏感性。因此，ROR2作为在多种肿瘤中表观遗传失活的抑癌基因，拮抗β-catenin和AKT信号通路，其表观遗传沉默可能作为肿瘤潜在的分子标志物和治疗靶。该研究进一步完善了受体酪氨酸激酶家族甲基化修饰的抑癌基因谱，这将为其在肿瘤侵袭转移中的生物学功能提供新的实验证据，有助于全面理解表观遗传修饰异常在肿瘤癌变过程中的重要作用，为发展肿瘤早期诊断、预防、治疗和预后分子诊断的提供重要实验依据。