Rab37基因启动子高甲基化在鼻咽癌转移中的作用及分子机制研究

Distant metastasis is the main reason for the treatment failure of naopharyngeal carcinoma. Conducting in-depth research on the molecular mechanism of the key molecular markers in the metastatic process, is an important way to achieve individualized treatment of nasopharyngeal carcinoma and reduce its distant metastasis rate. Changes of DNA methylation may play important roles in nasopharyngeal carcinoma metastasis. We have confirmed that Rab37 gene was hypermethylated in NPC by genome-wide methylation array screening method, which was related with poorer prognosis. The migration ability of NPC cells were inhibited in transfected CNE2 cell lines with Rab37 over-expression plasmid. However, the exact mechanisms are unknown. In this project, firstly, we will study the functions and mechanisms of Rab37 gene in NPC metastasis in vitro and in vivo, which may help to provide potential new targets for individual therapy. Then we will further examine the Rab37 promoter methylation status in 350 NPC patients with matched clinical data, and evaluated its prognostic value.

远处转移是制约鼻咽癌疗效提高的瓶颈，从分子水平深入研究导致鼻咽癌转移的关键分子，是实现鼻咽癌个体化治疗、降低转移率的重要途径。DNA 甲基化改变在鼻咽癌的转移中可能发挥重要作用。我们的前期研究显示：1）利用全基因组甲基化芯片和qPCR检测发现鼻咽癌组织中Rab37基因高甲基化且mRNA表达水平减少，临床资料显示Rab37基因高甲基化的患者预后较差；2）降低Rab37在鼻咽癌细胞中的表达可以抑制细胞的侵袭转移，但其具体功能及机制尚不清楚。本申请项目拟在此基础上：1）检测350例鼻咽癌组织中Rab37基因启动子区甲基化状态，研究其对鼻咽癌患者预后的预测价值；2）在体内外模型中研究Rab37基因在鼻咽癌抑制侵袭转移的具体功能及机制。以此明确Rab37基因甲基化对鼻咽癌患者预后的预测价值，阐明其在鼻咽癌转移中的功能及分子机制，为鼻咽癌“个体化”治疗提供新的靶点。

表观遗传改变通过基因调控在肿瘤转移和耐药中发挥重要作用。然而，表观遗传改变在鼻咽癌转移中的功能与分子机制尚不清楚。本课题研究发现Rab37是鼻咽癌中最常见的下调基因。Rab37的下调归因于其启动子的高甲基化，并且与鼻咽癌转移及多西他赛耐药相关。Rab37高表达会抑制鼻咽癌细胞转移，增强对多西他赛的敏感性。在机制上，Rab37调节TIMP2分泌，抑制下游MMP2活性，从而调控鼻咽癌细胞的转移。此外，Rab37高甲基化与鼻咽癌患者的不良预后相关。研究表明Rab37高甲基化与鼻咽癌的转移和化疗耐药有关，基于RAB37甲基化和N分期的预后模型可以预测了鼻咽癌患者远处转移风险和对含多西他赛诱导化疗的疗效。