Uhrf2基因在小鼠结直肠癌中的功能和机制研究

发布时间：2018-05-03 13:49

本文选题：Uhrf2 + 结直肠癌　；参考：《华东师范大学》2016年硕士论文

【摘要】：结直肠癌以其高患病率和死亡率成为全球健康难题,是全球第三大恶性癌症。结直肠癌的发生发展是多种基因遗传突变以及表观遗传异常积累的结果。Ubiquitin-like with PHD and ring finger domains 2(Uhr(基因能编码含有多个功能结构域的核蛋白,在细胞周期调控和表观遗传学中起到重要作用,过表达Uhrf2能引起G1期细胞周期阻滞。提示Uhrf2可能在结直肠癌发生发展过程中发挥作用。Uhrf2作为一个新近发现的基因,在结直肠癌发生发展方面的功能和机制都不清楚。本课题构建了Uhrf2-Lac 报告基因小鼠,同时利用最新的CRISPR/Cas9基因组编辑技术,构建了Uhrf2基因敲除小鼠。通过X-gal染色发现Uhrf2在肠组织中主要表达在肠上皮的肠隐窝的干细胞和前体细胞(TA细胞)区域,暗示其可能与肠上皮细胞的增殖相关。Uhrf2敲除小鼠能正常存活,没有明显缺陷。组织形态学分析发现敲除Uhrf2对小鼠小肠和结肠上皮细胞的增殖分化没有影响。通过DSS处理的急性肠炎模型,发现Uhrf2缺失不影响肠炎的发生和组织修复。为了研究Uhrf2在肠癌中的功能,将突变小鼠与ApcMin/+小鼠杂交得到Apc~(Min/+) Uhrf2~(-/-)双基因突变动物。对5周大小的对照组和实验组小鼠肠肿瘤的数量、分布情况(小肠近端、中端、远端)和直径大小分析,发现敲除Uhrf2能够显著抑制肠肿瘤的发生发展,证实敲除Uhrf2能够抑制肠肿瘤发生的早期阶段。我们还对敲除Uhrf2能够抑制肠肿瘤发生发展的机制进行了初步研究。由于敲除Uhrf2不影响肠上皮的稳态维持与损伤修复而限制抑制肿瘤的发生,提示该基因是肠癌治疗的潜在药物作用靶点。
[Abstract]:Colorectal cancer, with its high prevalence and mortality, is a global health problem and the third largest cancer in the world. The development of colorectal cancer is the result of multiple genetic mutations and epigenetic abnormal accumulation of.Ubiquitin-like with PHD and ring finger domains 2 (Uhr (based on the encoding of multiple functional domains of nuclear eggs) White, which plays an important role in cell cycle regulation and epigenetics, overexpression of Uhrf2 can cause cell cycle arrest in G1 phase. It suggests that Uhrf2 may play a role in the development of colorectal cancer as a newly discovered gene, and the function and mechanism of the development of colorectal cancer are not clear. Uhrf2-Lac gene mice were reported, and Uhrf2 gene knockout mice were constructed using the latest CRISPR/Cas9 genome editing technique. X-gal staining showed that Uhrf2 was mainly expressed in the intestinal crypts of the intestinal epithelium and the region of the precursor cells (TA cells) in the intestinal epithelium, suggesting that it might be associated with the proliferation of the intestinal epithelial cells in.Uhrf2 knockout. The mice were able to survive without obvious defects. Histomorphological analysis found that knockout Uhrf2 had no effect on the proliferation and differentiation of the intestinal and colonic epithelial cells in mice. The DSS treatment model of acute enteritis showed that the deletion of Uhrf2 did not affect the occurrence of enteritis and tissue repair. In order to study the function of Uhrf2 in colorectal cancer, the mutant mice and ApcMi were used to study the function of the mutant mice. N/+ mice were hybridized with Apc~ (Min/+) Uhrf2~ (- / -) double gene mutation. The number and distribution of intestinal tumors in the 5 week size control group and experimental group (small intestine near, middle, distal) and diameter were analyzed. It was found that knockout Uhrf2 could significantly inhibit the development of intestinal tumor, and it was proved that knockout Uhrf2 could inhibit the occurrence of intestinal tumor. In the early stage, we also had a preliminary study on the mechanism that Uhrf2 could inhibit the occurrence and development of intestinal tumor. Because the knockout of Uhrf2 did not affect the homeostasis of the intestinal epithelium and the repair of injury, we suggested that the gene is a potential drug target for the treatment of colon cancer.

【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R735.34

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