本文選題：RNA干涉　切入點：小發(fā)夾RNA　出處：《山東大學(xué)》2006年博士論文　論文類型：學(xué)位論文

【摘要】：EB病毒(Epstein-Barr virus，EBV)是重要的DNA致瘤病毒，與多種人類惡性腫瘤如Burkitt淋巴瘤、鼻咽癌(NPC)、何杰金氏病、免疫缺陷病人的B淋巴細(xì)胞瘤、T淋巴細(xì)胞瘤、胃癌及肝癌等的發(fā)生有關(guān)。研究表明在EBV相關(guān)腫瘤組織中，EBV只感染癌細(xì)胞而不感染正常細(xì)胞，而EBV陽性癌組織中，EBV基因組存在于幾乎所有的癌細(xì)胞中，，提示EBV可能是治療EBV陽性腫瘤的理想靶點，因此可以利用EBV陽性腫瘤細(xì)胞與正常細(xì)胞的差異，采用適當(dāng)方法選擇性地殺傷EBV陽性的腫瘤細(xì)胞。腫瘤組織中EBV主要以潛伏感染的形式存在，不同EBV相關(guān)腫瘤組織中病毒潛伏感染狀態(tài)不同，所表達(dá)的癌基因也不完全相同。EBV潛伏膜蛋白基因LMP1和核抗原基因EBNA2是公認(rèn)的導(dǎo)致細(xì)胞惡性轉(zhuǎn)化的病毒癌基因。EBNA2為EBV轉(zhuǎn)化B淋巴細(xì)胞過程中最早表達(dá)的病毒編碼蛋白，通過增強(qiáng)細(xì)胞周期素D2的轉(zhuǎn)錄而活化細(xì)胞周期，并能增強(qiáng)LMP1對原癌基因bc1-2表達(dá)的誘導(dǎo)作用。LMP1高水平表達(dá)可誘發(fā)細(xì)胞癌變，在B淋巴細(xì)胞的體外轉(zhuǎn)化中起重要作用，還可抑制人上皮細(xì)胞的分化，誘導(dǎo)人上皮細(xì)胞和大鼠細(xì)胞在裸鼠體內(nèi)形成腫瘤，并可通過激活A(yù)20基因阻斷p53介導(dǎo)的細(xì)胞凋亡，但某些EBV陽性腫瘤中檢測不到LMP1的表達(dá)。近年來EBV早期基因BHRF1的致癌作用亦逐漸受到關(guān)注。BHRF1是EBV裂解早期表達(dá)的蛋白，位于EBV基因組第54376至54951位核苷酸區(qū)域，全長576bp，開放讀碼框有191個密碼子，編碼17kDa的蛋白質(zhì)，屬于Bc1-2家族。BHRF1與細(xì)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兩者的BH1、BH2區(qū)和C末端。實驗表明BHRF1除具有與bc1-2相似的抑制B淋巴細(xì)胞和上皮細(xì)胞凋亡的作用外，又具有bc1-2所沒有的促進(jìn)細(xì)胞生長
[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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2006
【分類號】：R373.21

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