雌激素撤退对BRAF激活性突变后结肠CIMP+/MSI-H肿瘤发生的影响

CIMP was an important epigenetic phenotype of colonic mucosa, but its essential characteristics still needed clarification. How the CIMP happened and what methylation details determined the progression of the CIMP pathway were far from being disclosed.Inspired by the fact that CIMP+/MSI-H tumors as a typical phenotype group in CIMP pathway happened much more often in postmenopause population,we studied the effects of inhibition of estrogen signaling pathway on the CIMP development. we found that it could induce the gene methylation but need the help of other cancer promotor to gain a phenotype change. Since the BRAFV600E had been verified to be essential for the CIMP+/MSI-H tumor development and capable to influence the gene methylation in colon cancer cells, its epigenetic effects were studied in combination with estrogen withdrawal. The pangenomic methylation pattern and detailed methylation profile of hMLH1 gene promotor were analyzed to draw out some data about the methylation trait and cellular biological effects of the two vital causative factors on colonic cells. The bioinformation data would be analyzed to find out some essential features of CIMP, and then to be verified in clinical speciments or cell models. Some features of the DNA methylation course would be explored to depicted a regulation pattern of the CIMP+/MSI development.

CIMP是结肠粘膜的一种重要表观遗传学表型，但其发生机制不明，其本质特征即哪些甲基化细节决定着CIMP途径的进程还不清楚。基于CIMP途径典型的CIMP+/MSI-H肿瘤在绝经后明显增加的现象，我们的研究发现，雌激素撤退或其受体表达失活，可促进结肠粘膜基因组甲基化的发生，但可能需其他促肿瘤因素的协同才能影响到表观遗传学表型。鉴于BRAF激活性突变已被证实是与CIMP+/MSI-H肿瘤的关键性增殖动力因素，并能影响结肠癌细胞的基因甲基化，所以本项目将其与雌激素水平撤退处理结合起来，模拟绝经后BRAF突变对结肠粘膜的影响，从全基因组甲基化模式及关键性的hMLH1基因启动子甲基化细节两个方面，分析CIMP+/MSI-H易患条件下基因组甲基化的特征性动态以及细胞生物学表现，以期解析出反映CIMP途径启动及预示其进展方向的一些关键性甲基化特征，阐明绝经后CIMP途径进展过程的调控方式。

CIMP是结肠粘膜的一种重要表观遗传学表型，但其发生机制不明，其本质特征即哪些甲基化细节决定着CIMP途径的进程还不清楚。基于CIMP途径典型的CIMP+/MSI-H肿瘤在绝经后明显增加的现象，我们的研究发现，雌激素撤退或其受体表达失活，可促进结肠粘膜基因组甲基化的发生，但可能需其他促肿瘤因素的协同才能影响到表观遗传学表型。鉴于BRAF激活性突变已被证实是与CIMP+/MSI-H肿瘤的关键性增殖动力因素，并能影响结肠癌细胞的基因甲基化，所以本项目将其与雌激素水平撤退处理结合起来，模拟绝经后BRAF突变对结肠粘膜的影响，分析CIMP+/MSI-H易患条件下基因组甲基化的特征性动态以及细胞生物学表现，以期解析出影响CIMP途径启动的一些关键性因素，阐明绝经后CIMP途径进展过程的调控方式。.通过本项目研究，我们在细胞模型和大鼠诱癌模型上证实，雌激素撤退与BRAFV600E突变，可协同影响结肠癌的发生，在信号通路方面的影响，主要在于与p53相关的凋亡过程中，在表观遗传学影响方面，已筛选出包括SYNE1、TEM8在内的8个基因，受其影响可能比hMLH1、p16基因等更明显，进一步的生物信息分析，SYNE1基因可能在雌激素与BRAF突变的表观遗传学作用中，发挥重要作用，值得进一步研究。