抑癌性微小RNA-145/143表达异常在新疆地区女性子宫内膜增生癌变中的功能与作用机制研究

Type I tumors with endometrioid histology account for the majority of endomtrial carcinomas and frequently are preceded by premalignant hyperplasia. Endometrial cancer are more common in Han women than in Uygur women in Xinjiang. And pooly-differented tumors occur more often in Han women, on the contray, well-differented tumors occur more often in Uygur women. It is well known that the role of epigenetic modification in endometrial carcinogenesis, especially in its early stage, has been suggested. In previous study we have found that two tumor suppressors miRNAs, miR-145/143, targeting DNA methyltransferases (DNMT3B, 3A) downregulated in endomtrioid endometrial adenocarcinoma (EEC) of Han women as well as in Uygur women by real-time PCR based assays. Moreover, miR-145 downregulation ocurred more often in Han women, whereas miR-143 downregulation happened more frequently in Uygur wemen. Furthermore, we identified the correlation between DNMT3B overexpression and PTEN and MMR downexpression in Han women with EEC. PTEN and MMR funcation loss are most common molecular events in endometrial carcinogenesis. Taken together, in this study, we will further investigate and confirm our hypothesis that the miR-145/143 play a vital role in endometrial carcinogensis through regulating DNMT expression and thereby inducing promoter altered methylation and silencing PTEN and MMR expression in type I endometrial carcinomas. Furthermore, we will try to compare and discover the distribution and contribution of these early molecular events in the process of endometrial carcinogesis in Han women and Uygur women in order to elucidate the differences of their function and mechanism in endometrioid adenocarcinoma of Han and Uygur women. The findings of this study will reflect the important molecular insights into type I endometrial cancer of Han and Uygur women. The results of this study will give cludes on the role of miR-145/143 in Han and Uyger women with EEC and will provide a development of miRNA-based targeted approaches for the treatment of endometrial cancer.

I型癌占子宫内膜癌绝大多数，常由癌前增生发展所至。新疆地区汉族女性内膜癌显著高于维族，且分化差的肿瘤主要见于汉族。已知表观遗传调控机制在I型癌发病中扮演重要角色。我们前期发现与DNA甲基转移酶（DNMT3B,3A）调节有关的微小RNA－miR-145/143在维汉女性内膜癌均特异表达降低；但汉族miR-145降低更显著，维族miR-143降低更显著。汉族女性DNMT3B高表达与I型癌高发分子事件PTEN和MMR基因hMLH1低表达有关。本研究将在前期基础上，确定I型癌miR-145或143低表达解除对DNMT3B或3Ａ的表达抑制，导致启动子甲基化是内膜癌发病中PTEN和MMR功能缺陷的重要调控机制；对比分析miR-145, 143及相关分子在维汉女性内膜增生癌变中作用规律与差异，本研究将揭示维汉女性I型癌miR-143或145 作用机制与功能差异，为探索逆转内膜增生癌变的治疗新靶点提供依据

子宫内膜癌发病具有地域地点，统计近年来新疆医科大学附属肿瘤医院数据显示汉族女性内膜癌显著高于维族女性，且淋巴转移率高。本研究探讨miRNA表达、DNA甲基转移酶及激素等因素在维汉女性子宫内膜癌发生发展中的作用机制与差异。我们发现：1、维汉女性内膜癌miRNA表达谱存在一定差异。相对于正常对照，23个miRNA在两民族I间表达截然相反；35个miRNA表达类似；但多数miRNA在一个民族中表达显著异常，而在另一个民族中不表达或变化轻微（93和90）。2、进一步验证提示miR-143, miR-145在两民族表达特点相反，维族升高，汉族降低。miR-141, miR200a, miR-205两个民族均显著高表达，但扮演角色不尽相同。3、miR-145可抑制内膜癌细胞的增殖、迁移和浸润能力。而miR-143仅抑制迁移和浸润能力。miR-145可抑制HER -2蛋白表达，而miR-143显著抑制HER-2下游PI3K通路关键分子表达。4、DNMT3B是miR-143及miR-145的共同预测靶基因之一。双萤光素酶报告基因提示miR143,145与DNMT3B-3’UTR特异结合。汉族I型癌（EC）中，miR-143和miR-145与DNMT3B存在负相关，且提示预后差。II型癌（NEC）不存在此特点。维族内膜癌也存在DNMT3B过表达但与miR-145／143不相关。5、miR-141/200a两民族均表达升高，但维族EC，这两个miRNA表达水平高的肿瘤更具侵袭性；但汉族相反miR-200a 表达水平高的肿瘤趋向温和。miR-141/ 200a与激素受体的关系，两民族特点一致。EC中与激素受体正相关；NEC中与激素受体呈负相关趋势。提示I型癌ER或PR可能是miR-141, 200a高表达的正向调控因素；而II型癌miR-141, 200a高表达可能是雌孕激素受体失表达的机制之一。..综上，本研究提示维汉女性内膜癌发病特点不同， miRNA表达差异及功能作用机制差异可能与之有关。汉族I型癌中miR-143/145低表达，通过解除对靶基因DNMT3B抑制，导致DNMT3B表达升高，可能导致一些重要基因甲基化和功能缺失，可能是汉族I型癌发病的重要机制。而维族II型癌miR-143/145表达升高具有保护性作用。miR-141/200a两民族均表达升高，但功能有所不同。