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特异性沉默EBV潜伏期基因BHRF1pSUPER retro RNAi系统的构建和初步应用

发布时间:2018-03-12 08:46

  本文选题:RNA干涉 切入点:小发夹RNA 出处:《山东大学》2006年博士论文 论文类型:学位论文


【摘要】:EB病毒(Epstein-Barr virus,EBV)是重要的DNA致瘤病毒,与多种人类恶性肿瘤如Burkitt淋巴瘤、鼻咽癌(NPC)、何杰金氏病、免疫缺陷病人的B淋巴细胞瘤、T淋巴细胞瘤、胃癌及肝癌等的发生有关。研究表明在EBV相关肿瘤组织中,EBV只感染癌细胞而不感染正常细胞,而EBV阳性癌组织中,EBV基因组存在于几乎所有的癌细胞中,,提示EBV可能是治疗EBV阳性肿瘤的理想靶点,因此可以利用EBV阳性肿瘤细胞与正常细胞的差异,采用适当方法选择性地杀伤EBV阳性的肿瘤细胞。肿瘤组织中EBV主要以潜伏感染的形式存在,不同EBV相关肿瘤组织中病毒潜伏感染状态不同,所表达的癌基因也不完全相同。EBV潜伏膜蛋白基因LMP1和核抗原基因EBNA2是公认的导致细胞恶性转化的病毒癌基因。EBNA2为EBV转化B淋巴细胞过程中最早表达的病毒编码蛋白,通过增强细胞周期素D2的转录而活化细胞周期,并能增强LMP1对原癌基因bc1-2表达的诱导作用。LMP1高水平表达可诱发细胞癌变,在B淋巴细胞的体外转化中起重要作用,还可抑制人上皮细胞的分化,诱导人上皮细胞和大鼠细胞在裸鼠体内形成肿瘤,并可通过激活A20基因阻断p53介导的细胞凋亡,但某些EBV阳性肿瘤中检测不到LMP1的表达。近年来EBV早期基因BHRF1的致癌作用亦逐渐受到关注。BHRF1是EBV裂解早期表达的蛋白,位于EBV基因组第54376至54951位核苷酸区域,全长576bp,开放读码框有191个密码子,编码17kDa的蛋白质,属于Bc1-2家族。BHRF1与细胞原癌基因bc1-2的序列具有高度同源性,同源序列主要集中在两者的BH1、BH2区和C末端。实验表明BHRF1除具有与bc1-2相似的抑制B淋巴细胞和上皮细胞凋亡的作用外,又具有bc1-2所没有的促进细胞生长
[Abstract]:Epstein-Barr virus (EBV) is an important DNA tumorigenic virus associated with various human malignant tumors such as Burkitt lymphoma, nasopharyngeal carcinoma (NPC), Hodgkin's disease, and immunodeficient patients with B lymphocyte tumor T lymphocyte tumor. Studies have shown that EBV only infects cancer cells and does not infect normal cells in cancer tissues associated with EBV, while the genome of EBV positive cancer tissues is present in almost all cancer cells. The results suggest that EBV may be an ideal target for the treatment of EBV positive tumors, so the difference between EBV positive tumor cells and normal cells can be exploited. EBV positive tumor cells were selectively killed by appropriate methods. EBV mainly existed in the form of latent infection in tumor tissues, and the virus latent infection status was different in different EBV related tumor tissues. EBV latent membrane protein gene (LMP1) and nuclear antigen gene (EBNA2) are recognized as viral oncogenes. EBNA2 is the earliest expressed viral coding protein in the process of EBV transformation into B lymphocytes. By enhancing the transcription of cyclin D2 and enhancing the induction of bc1-2 expression by LMP1, the high level expression of LMP1 can induce cell carcinogenesis and play an important role in the transformation of B lymphocytes in vitro. It can also inhibit the differentiation of human epithelial cells, induce human epithelial cells and rat cells to form tumors in nude mice, and block the apoptosis mediated by p53 by activating A20 gene. However, the expression of LMP1 was not detected in some EBV positive tumors. In recent years, the carcinogenicity of BHRF1, an early EBV gene, was gradually concerned. BHRF1 was expressed in the early stage of EBV cleavage, and was located in the 54376 to 54951 nucleotide region of EBV genome. The full length 576bp, open reading code frame has 191 codon, encode 17kDa protein, belong to Bc1-2 family. BHRF1 has high homology with the bc1-2 sequence of cell oncogene. The homologous sequences were mainly located in the BH1 / BH2 region and the C-terminal region. The results showed that BHRF1 not only inhibited the apoptosis of B lymphocytes and epithelial cells similar to bc1-2, but also promoted cell growth that bc1-2 did not.
【学位授予单位】:山东大学
【学位级别】:博士
【学位授予年份】:2006
【分类号】:R373.21

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