TET1通过诱导抑癌基因Rassf5上调从而抑制卵巢癌细胞增殖的研究

发布时间：2019-04-07 15:49

【摘要】：卵巢癌是危害妇女健康最常见的恶性肿瘤之一,其致死率在所有妇科癌症中居于首位,卵巢癌发病隐蔽,极易发生侵袭和转移,约70%患者就诊时已处于晚期阶段,因此,卵巢癌患者的5年生存率仅30%左右。抑癌基因启动子区域的DNA高甲基化与该基因转录抑制密切相关,并且被认为与多种肿瘤的发生发展有关。TET(Ten eleven translocation)催化DNA的5-甲基胞嘧啶(5mC)发生氧化反应从而使DNA去甲基化。最新研究表明,Tet1表达下调与乳腺癌及结肠癌的恶性化有关。然而,TET1在卵巢癌细胞增殖中的作用仍不清楚。我们研究发现,Tet1和5hmC在人类卵巢癌组织及细胞系中表达量下降。并且CUL4-DDB1泛素连接酶复合体和TET1能调节人类卵巢癌细胞系中5hmC的含量。过表达TET1抑制卵巢癌细胞的增殖及克隆形成能力,RNAi敲降TET1促进卵巢癌细胞的增殖及克隆形成能力。裸鼠皮下成瘤结果显示,过表达TET1抑制裸鼠移植瘤生长,而RNAi敲降TET1促进裸鼠移植瘤生长。分子机制研究发现,过表达TET1导致Rassf5基因启动子区域去甲基化,开启Rassf5基因表达,从而发挥肿瘤抑制效应。由此可见,TET1导致的DNA羟甲基化对肿瘤生长起着重要作用。该论文有助于进一步了解卵巢癌发生发展的机理,为临床治疗卵巢癌提供了新的理论依据。
[Abstract]:Ovarian cancer is one of the most common malignant tumors that endanger women's health. The fatality rate of ovarian cancer is the highest among all gynecological cancers. The incidence of ovarian cancer is covert and prone to invasion and metastasis. About 70% of the patients are in the advanced stage of treatment, so, The 5-year survival rate of patients with ovarian cancer was only about 30%. The hypermethylation of DNA in the promoter region of the tumor suppressor gene is closely related to the transcriptional inhibition of the gene. Tet (Ten eleven translocation) catalyzes the oxidation of 5-methylcytosine (5mC) of DNA to demethylation of DNA. Recent studies have shown that down-regulation of Tet1 expression is associated with the malignant nature of breast and colon cancer. However, the role of TET1 in the proliferation of ovarian cancer cells is still unclear. We found that the expression of Tet1 and 5hmC decreased in human ovarian cancer tissues and cell lines. CUL4-DDB1 ubiquitin ligase complex and TET1 could regulate the content of 5hmC in human ovarian cancer cell line. Overexpression of TET1 inhibited the proliferation and clone formation of ovarian cancer cells, and RNAi down-regulated the ability of TET1 to promote the proliferation and clone formation of ovarian cancer cells. The results of subcutaneous tumorigenesis in nude mice showed that overexpression of TET1 inhibited the growth of transplanted tumor in nude mice, while RNAi down-regulated TET1 promoted the growth of transplanted tumor in nude mice. Molecular mechanism studies have shown that overexpression of TET1 leads to demethylation in the promoter region of Rassf5 gene and turns on the expression of Rassf5 gene, so as to play a tumor inhibitory effect. Therefore, TET1-induced DNA hydroxymethylation plays an important role in tumor growth. This paper is helpful to understand the pathogenesis of ovarian cancer and provide a new theoretical basis for clinical treatment of ovarian cancer.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.31

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