临床和流行病学研究证实雌激素有预防结直肠癌的效果，但具体机制不明确。我们前期研究发现，雌激素能上调结肠细胞错配修复基因hMLH1的表达，增强错配修复功能；而在hMLH1缺陷的结肠癌细胞株中再表达hMLH1，能明显增强雌激素诱导的凋亡。因此推测雌激素可能通过hMLH1基因促进了结肠细胞凋亡的发生，从而起到预防结直肠癌的作用。本项目将进一步研究hMLH1基因在雌激素诱导结肠细胞凋亡中的作用和分子机制。我们将首先在体外培养细胞中通过敲低和再表达，明确hMLH1表达对雌激素诱导结肠癌细胞凋亡的影响，然后通过检测凋亡信号分子的表达和活性明确其涉及的凋亡通路，并通过转录分析和免疫共沉淀研究hMLH1蛋白与凋亡信号分子相互作用的方式，最后在动物模型内验证雌激素对hMLH1和凋亡的影响。本研究是对雌激素预防结直肠癌机制的进一步探索，为雌激素类似物用于结直肠癌的化学预防提供理论依据。

Estrogen is reported to have a protective effect on colorectal cancer. However, the underlying mechanism is unclear. We have reported estrogen increased the expression of mismatch repair (MMR) gene hMLH1 as well as MMR function in colonic cells. And re-expressing hMLH1 in HCT116 cells can increase estrogen-induced apoptosis significantly. According to this, we supposed that estrogen might prevent colorectal cancer through hMLH1-dependent colonic cells apoptosis. In this study, we will assess the role of hMLH1 in estrogen-induced colonic cells apoptosis and the potential mechanism. Firstly, we will check whether hMLH1 participates in estrogen-induced apoptosis throuth knocking-down and re-expressing in cultured cells. Then the pathway involved in apoptosis will be checked through signaling molecules detection. Moreover, the interaction between hMLH1 protein and apoptosis signaling molecules will be investigated through transcription and co-immunoprecipitation analysis. Finally, we will check the results in animal models. This findings will be important in colorectal cancer chemoprevention by estrogen analogues.