囊泡运输和Ras/MAPK信号转导通路基因甲基化水平与大肠癌发病及预后的关系

Vesicle trafficking is mainly responsible for intracellular macromolecules transport and signal transduction et al. The transport barrier leads to various organelles defects and cell dysfunction, promote tumorigenesis, invasion and metastasis. Ras/MAPK signal transduction pathway regulates cell proliferation and apoptosis, promote tumorigenesis, invasion and metastasis. Ras of the Ras/MAPK pathway could mediate vesicle movement. Therefore, we infer that Vesicle trafficking and Ras/MAPK could jointly regulate intracellular signal transduction; synergistically promote malignant proliferation, invasion and metastasis of tumor cells. DNA methylation could affect gene transcription and lead to abnormal expression of protein, finally induce tumor. Yet no in vivo, in vitro study and epidemiologic study aimed to explore the relationship between the DNA methylation of vesicle trafficking and colorectal cancer. Oncogenes in Ras/MAPK pathway present hypomethylation, but no epidemiologic study aimed to explore the relationship between hypomethylation of Ras/MAPK and colorectal cancer risk and prognosis. Therefore, we carry out a case-control study to explore the associations between DNA methylation of Vesicle trafficking and Ras/MAPK and colorectal cancer risk, their interactions and their interactions with environmental factors on colorectal cancer risk; we then conduct a cohort study to explore the associations between DNA methylation of Vesicle trafficking and Ras/MAPK and colorectal cancer prognosis, their interactions and their interactions with environmental factors on colorectal cancer prognosis; hoping to explore the biomarker panels for early prevention and individualized treatment of colorectal cancer.

囊泡运输主要负责胞内物质运输、信号传递等，其运输障碍会导致多种细胞器缺陷和细胞功能紊乱，促进肿瘤发生、侵袭和转移。Ras/MAPK信号转导通路调控细胞增殖与凋亡，与肿瘤密切相关。Ras能调控囊泡转运。由此推测囊泡运输与Ras/MAPK共同调控胞内信号传递，协同促进肿瘤细胞恶性增殖、侵袭和转移。DNA甲基化可影响基因转录导致蛋白质表达异常，诱发肿瘤。囊泡运输相关基因甲基化与大肠癌关系的体内外及人群流行病学研究均未见报道。Ras/MAPK通路癌基因呈现低甲基化，但尚未有其与大肠癌关系的人群流行病学研究。本研究拟采用病例对照研究探索囊泡运输及Ras/MAPK通路基因甲基化、二者的交互作用及二者与环境因素的交互作用和大肠癌发病的关系；采用队列研究探索囊泡运输及Ras/MAPK通路基因甲基化、二者的交互作用及二者与环境因素的交互作用和大肠癌预后的关系；为大肠癌早期预防和个体化治疗提供理论依据。

本研究在外周血中开展较大样本的病例对照研究，研究囊泡运输与Ras/MAPK信号转导通路基因甲基化水平与大肠癌易感性的关系。在此基础上，本课题组还筛选了Ras/MAPK信号转导通路其他与肿瘤相关的基因，并在外周血中检测其甲基化的情况。采用队列研究的方法在组织及外周血中研究SEMA6B及PBX3基因甲基化水平与大肠预后的关系。此外，本课题组通过RRBS的方法进行大肠癌差异甲基化位点的筛选，进而为大肠癌的早期预防，尤其是针对不同启动子区CpG岛甲基化状况、不同分子分型的大肠癌进行个体化预防及临床治疗，改善预后提供指标。