受体表达增强蛋白诱导非小细胞肺癌上皮间质转化和促进肿瘤侵袭转移的分子机制

Metastasis of lung cancer, the spread of tumor cells from a primary tumor to a secondary site within the human body remains one of the most life-threatening events. In the early stage of metastasis, a process that is known as the epithelial-mesenchymal transition (EMT) is currently in the limelight of cancer cell migration, invasion and metastatic dissemination. However, the molecular processes underlying such cellular changes are still only poorly understood. Our research studies had shown that the expression of REEP6 was remarkably higher in the metastatic lymph nodes rather than the primary lesion of lung adenocarcinoma. Silencing REEP6 induced mesenchymal-epithelial transitions (MET) in lung cancer cells, and inhibited metastasis in vitro and in vivo. And more, we also found that REEP6 expression was correlated with Wnt/β-catenin signaling pathway, which was demonstrated as a critical regulatory mechanism controlling MET and metastasis. Receptor expression enhancing protein (REEP) family is found in the cell membrane and promotes functional cell surface expression of odorant receptors, but it was rarely investigated in the cancer research field. On the basis of these results, we propose following hypothesis: REEP6 activates Wnt/β-catenin signaling pathway by enhancing the expression of Wnt receptors on the cell membrane, thus leading epithelial-mesenchymal transitions of lung cancer cells and promoting tumor metastasis. The finding of this study will help elucidate the mechanism underlying EMT and metastasis, and indicate that REEP6 may use as a new significant prognostic indicator and therapeutic target for lung cancer.

转移是导致肺癌复发和患者死亡的主要原因。在转移早期，上皮来源的肿瘤细胞发生上皮间质转化 (EMT)，被认为是肿瘤转移的基础。但诱导肿瘤发生EMT的分子调控机制仍不清楚。前期研究表明受体增强蛋白家族成员REEP6在肺癌淋巴结转移灶中的表达明显高于原位癌组织；体内外实验证明沉默REEP6的表达使肺癌细胞从间质细胞表型向上皮细胞表型转化，并抑制肿瘤细胞的转移；也表明REEP6与调控EMT过程的Wnt/β-catenin信号通路相关。受体表达增强蛋白是新发现的可增强嗅觉受体表达的蛋白家族，在肿瘤研究领域还鲜有报道。我们提出以下假说：REEP6 通过增强Wnt受体在细胞膜上的表达而激活Wnt/β-catenin信号通路，从而诱导肺癌细胞的上皮间质转化，促进肿瘤的转移。本课题将有助于阐明肺癌EMT和复发转移的调控机制，为REEP6是否可作为预后判断及治疗的潜在分子靶点提供理论依据，具有重要的研究意义。

肺癌是发病率和死亡率最高的恶性肿瘤。研究促进肺癌发展的关键调控因子的生物学功能及分子作用机制，寻找肺癌的精准诊疗中的分子靶点和标志物，建立精准的预后模型，具有重要的临床研究意义和应用前景。. 本研究在mRNA和蛋白表达层面均证明受体表达增强蛋白家族成员REEP2在肺腺癌里高表达，蛋白表达水平与淋巴结转移、远处转移、临床TNM分级，患者生存预后的相关；细胞功能性实验证明REEP2表达与上皮间质转化相关，促进细胞的迁移侵袭能力；REEP2表达调控差异基因的GO聚类、KEGG和GSEA信号通路分析结果显示发现REEP2表达与肺部疾病，多种肿瘤发生发展相关；与跨膜转运、细胞外基质的合成、细胞外基质的结构以及ERK信号通路、Wnt/beta-catenin信号通路、I型干扰素信号通路相关；与细胞内药物代谢、细胞内代谢及细胞因子与受体相互作用、细胞外基质与受体的相互作用相关。研究结果为 REEP2 作为临床非小细胞肺癌预后判断及治疗的潜在的分子靶点提供理论依据。. 研究还对临床肺癌诊疗过程中遇到的实际难题进行研究，探讨非小细胞肺癌的精准诊疗新分子标志物的临床应用价值和构建有价值的预测模型。研究中，项目组构建多元因素预测模型对肺癌免疫治疗标志物-肿瘤基因突变负荷进行预测，研究以叶酸受体作为标志物的循环肿瘤细胞在早期肺腺癌辅助诊断及术后监测中的应用价值，评估肺癌靶向药物克唑替尼生物标志物ROS-1蛋白阳性表达与ROS-1融合基因突变一致性。研究成果具有促进肺癌精准诊疗的应用价值及前景。.