發(fā)布時(shí)間：2018-05-08 03:22

  本文選題：RNF2 + MANF　； 參考：《安徽醫(yī)科大學(xué)》2015年碩士論文

【摘要】：環(huán)指蛋白2(ring finger protein 2,Ring2又稱RNF2或Ring1b)是一個(gè)具有環(huán)指(ring finger)結(jié)構(gòu)的泛素連接酶(E3),屬于多梳蛋白家族(polycomb group,Pc G)中多梳抑制子復(fù)合物1(polycomb repressor complex 1,PRC1)中的一員,可介導(dǎo)組蛋白H2A的第119位賴氨酸的泛素化,從而影響染色質(zhì)的結(jié)構(gòu),具有基因轉(zhuǎn)錄抑制的作用。Pc G家族中的很多蛋白都與腫瘤的發(fā)生和發(fā)展具有密切聯(lián)系,而關(guān)于RNF2在肝細(xì)胞癌(hepatocellular carcinoma,HCC)中所起的作用及其具體機(jī)制仍不明確。RNF2作為一個(gè)通過(guò)酵母雙雜交篩選出的與中腦星形膠質(zhì)細(xì)胞源性神經(jīng)營(yíng)養(yǎng)因子(mesencephalic astrocyte-derived neurotrophic factor,MANF)具有相互作用的蛋白,在HCC細(xì)胞和組織中也與MANF存在密切的相關(guān)性。MANF是一種可被內(nèi)質(zhì)網(wǎng)應(yīng)激(Endoplasmic reticulum stress,ERS)所誘導(dǎo)的分泌性蛋白,我們的研究發(fā)現(xiàn)其對(duì)HCC也有抑制作用。而RNF2可劑量依賴性的調(diào)節(jié)MANF的蛋白水平,因此我們推測(cè)RNF2對(duì)HCC的抑制作用可能是通過(guò)與MANF的相互作用而實(shí)現(xiàn)。目的:1.觀測(cè)RNF2在人肝細(xì)胞癌及非癌組織中的表達(dá)及與病人預(yù)后的關(guān)系;2.研究RNF2對(duì)肝癌細(xì)胞的影響;3.證明RNF2和MANF的相互作用;方法:在SMMC-7721細(xì)胞和TEL-7402細(xì)胞中,采用MTT實(shí)驗(yàn)、流式細(xì)胞術(shù)、免疫印跡法檢測(cè)caspase-3等方法證明RNF2對(duì)肝癌細(xì)胞的增殖和凋亡的影響;用平板實(shí)驗(yàn)、軟克隆瓊脂實(shí)驗(yàn)、劃痕實(shí)驗(yàn)、Transwell實(shí)驗(yàn)等研究RNF2對(duì)肝癌細(xì)胞的抑制作用;采用細(xì)胞免疫熒光、組織免疫熒光、組織免疫共沉淀驗(yàn)證RNF2和MANF在HCC中的相互作用;分別用tunicamycin(TM)和oxygen glucose deprivation(OGD)處理SMMC-7721和TEL-7402細(xì)胞,模擬HCC病人體內(nèi)的應(yīng)激和缺糖缺氧狀態(tài),在沉默和過(guò)表達(dá)RNF2之后,用RT-PCR和Western blot方法檢測(cè)MANF的基因和蛋白表達(dá)情況;在SMMC-7721細(xì)胞中分別轉(zhuǎn)染RNF2-myc質(zhì)粒(0μg,0.25μg,0.5μg,1.0μg),并分別用TM和OGD處理之后,用免疫印跡實(shí)驗(yàn)檢測(cè)MANF的蛋白表達(dá)情況。結(jié)果:1.RNF2在人肝細(xì)胞癌和非癌肝臟組織中的表達(dá)用免疫組織化學(xué)技術(shù)檢測(cè)RNF2在150例的肝細(xì)胞癌病人和136例的非腫瘤對(duì)照肝臟組織中的表達(dá)情況。結(jié)果發(fā)現(xiàn),RNF2在所有的病例中都有表達(dá),且與非癌對(duì)照比較,肝細(xì)胞癌病人的肝臟組織中RNF2高表達(dá)的比率顯著下降(p0.01)。2.RNF2可以增加糖氧剝奪(OGD)處理后肝癌細(xì)胞的死亡在SMMC-7721細(xì)胞中瞬時(shí)轉(zhuǎn)染RNF2的過(guò)表達(dá)質(zhì)粒以及si RNA,經(jīng)OGD處理2.5 h之后,用PI對(duì)其進(jìn)行染色,對(duì)視野下紅色的PI陽(yáng)性細(xì)胞進(jìn)行計(jì)數(shù),并進(jìn)行統(tǒng)計(jì)分析。結(jié)果發(fā)現(xiàn)過(guò)表達(dá)RNF2之后,死亡細(xì)胞增加;沉默了RNF2之后,死亡細(xì)胞減少,提示RNF2可能會(huì)促進(jìn)在缺糖缺氧情況下肝癌細(xì)胞的死亡。3.RNF2促進(jìn)SMMC-7721細(xì)胞的凋亡SMMC-7721細(xì)胞中轉(zhuǎn)染RNF2-si RNA質(zhì)粒并經(jīng)過(guò)OGD處理,然后用流式細(xì)胞儀檢測(cè)細(xì)胞的凋亡情況,用免疫印跡技術(shù)檢測(cè)caspase-3的表達(dá)情況。結(jié)果RNF2可以促進(jìn)OGD誘導(dǎo)的細(xì)胞凋亡及caspase-3的表達(dá)。4.RNF2對(duì)HCC細(xì)胞惡性行為學(xué)的影響4.1 RNF2抑制肝癌細(xì)胞的增殖在SMMC-7721和TEL-7402細(xì)胞中分別轉(zhuǎn)染RNF2-siRNA和RNF-myc質(zhì)粒,用MTT法及克隆形成實(shí)驗(yàn),分別檢測(cè)各組細(xì)胞的OD值以及單個(gè)細(xì)胞克隆形成能力。結(jié)果發(fā)現(xiàn)在沉默RNF2之后,細(xì)胞的增殖能力增加,過(guò)表達(dá)RNF2使細(xì)胞的增殖能力減弱。用流式細(xì)胞儀檢測(cè)細(xì)胞的活力也發(fā)現(xiàn)在沉默RNF2之后,細(xì)胞的增殖能力增加。4.2 RNF2抑制肝癌細(xì)胞的遷移能力用劃痕實(shí)驗(yàn)觀測(cè)了分別轉(zhuǎn)染RNF2-si RNA和RNF2-myc質(zhì)粒的肝癌細(xì)胞的遷移能力。結(jié)果發(fā)現(xiàn)沉默了RNF2之后,細(xì)胞的遷移能力增強(qiáng),而過(guò)表達(dá)RNF2使細(xì)胞的遷移能力減弱,該結(jié)果提示RNF2對(duì)肝癌細(xì)胞的遷移具有抑制作用。4.3 RNF2對(duì)肝癌細(xì)胞的侵襲能力具有抑制作用在分別沉默和過(guò)表達(dá)RNF2的SMMC-7721和TEL-7402細(xì)胞中,用transwell實(shí)驗(yàn)方法檢測(cè)細(xì)胞的侵襲能力,結(jié)果表明在沉默了RNF2的細(xì)胞組中,穿過(guò)T4小孔的細(xì)胞數(shù)比轉(zhuǎn)染載體對(duì)照的細(xì)胞增多;相反,過(guò)表達(dá)RNF2可抑制細(xì)胞的遷移,提示RNF2可以抑制肝癌細(xì)胞的侵襲能力。5.RNF2和MANF在SMMC-7721細(xì)胞核中共定位SMMC-7721細(xì)胞經(jīng)TM處理6 h或者經(jīng)OGD處理2.5 h之后,用免疫熒光雙標(biāo)觀察RNF2和MANF的表達(dá)情況。結(jié)果發(fā)現(xiàn),肝癌細(xì)胞經(jīng)上述處理之后,MANF和RNF2在細(xì)胞核中共定位。6.RNF2和MANF在HCC病人的肝臟組織中共定位肝細(xì)胞癌病人的肝臟組織經(jīng)包埋切片之后,用免疫熒光雙標(biāo)方法檢測(cè)RNF2和MANF在組織中的表達(dá)情況。結(jié)果表明兩者在肝癌組織中也存在共定位現(xiàn)象。7.RNF2和MANF在肝組織中的相互作用為觀察RNF2和MANF在肝癌組織中是否存在相互作用,我們將肝癌組織研磨提取蛋白之后進(jìn)行免疫共沉淀實(shí)驗(yàn)。用RNF2抗體沉淀組織中的RNF2蛋白,用IB檢測(cè)免疫沉淀物中是否有MANF;同時(shí)用抗MANF的抗體共沉淀RNF2。結(jié)果提示,RNF2可以與MANF在肝癌組織中相互作用。8.RNF2不影響MANF基因的轉(zhuǎn)錄在SMMC-7721細(xì)胞中沉默RNF2或者轉(zhuǎn)染過(guò)表達(dá)RNF2的質(zhì)粒,用RT-PCR的方法檢測(cè)MANF基因的表達(dá)水平。結(jié)果發(fā)現(xiàn)無(wú)論是在沉默RNF2還是過(guò)表達(dá)RNF2的細(xì)胞中,與對(duì)照組相比MANF的m RNA水平幾乎保持不變。9.RNF2影響MANF的蛋白水平在SMMC-7721細(xì)胞中,瞬時(shí)轉(zhuǎn)染RNF2-si RNA或RNF2-myc質(zhì)粒,采用免疫印跡方法檢測(cè)MANF的蛋白表達(dá)水平。結(jié)果表明在沉默RNF2之后MANF的表達(dá)下調(diào);而在過(guò)表達(dá)RNF2之后MANF的表達(dá)上調(diào);用細(xì)胞免疫熒光方法檢測(cè)MANF的表達(dá)水平,發(fā)現(xiàn)在RNF2被沉默的細(xì)胞中,MANF的表達(dá)也低,而在RNF2被過(guò)表達(dá)的細(xì)胞中,MANF的表達(dá)量也上調(diào)。10.RNF2劑量依賴性的調(diào)節(jié)MANF的蛋白水平在SMMC-7721細(xì)胞中分別轉(zhuǎn)染RNF2-myc質(zhì)粒0μg、0.25μg、0.5μg、1.0μg,并分為對(duì)照組、TM刺激組(6 h)、OGD刺激組(2.5 h),用免疫印跡方法來(lái)檢測(cè)MANF的蛋白表達(dá)情況。結(jié)果發(fā)現(xiàn),隨著RNF2-myc轉(zhuǎn)染劑量的逐漸增加MANF的蛋白水平也逐漸增加。提示MANF在蛋白水平上對(duì)RNF2存在劑量依賴性。結(jié)論:1.RNF2促進(jìn)肝癌細(xì)胞的凋亡;2.RNF2對(duì)HCC起抑制作用;3.RNF2和MANF在HCC中有相互作用;4.RNF2不影響MANF基因的轉(zhuǎn)錄,但可劑量依賴性的上調(diào)MANF的蛋白水平。
[Abstract]:The ring finger protein 2 (ring finger protein 2, Ring2 also known as RNF2 or Ring1b) is a ubiquitin ligase (E3) with the structure of the ring finger (ring finger), belonging to a member of the multi comb protein family (Polycomb group, Pc) 1, which mediates the ubiquitination of the 119th bit lysine of the histone As a result, the structure of chromatin is influenced by the inhibition of gene transcription, many of the proteins in the.Pc G family are closely related to the occurrence and development of tumor, and the role of RNF2 in hepatocellular carcinoma (HCC) and its specific mechanism are still not clearly defined by.RNF2 as a yeast two hybrid. The proteins interacting with mesencephalic astrocyte-derived neurotrophic factor (MANF), and the close correlation with MANF in HCC cells and tissues,.MANF is a secretory protein that can be induced by endoplasmic reticulum stress (Endoplasmic reticulum stress, ERS). The study found that it has a inhibitory effect on HCC, and RNF2 can be dose-dependent to regulate the protein level of MANF. Therefore, we speculate that the inhibitory effect of RNF2 on HCC may be achieved through the interaction with MANF. Objective: 1. to observe the expression of RNF2 in human hepatocellular carcinoma and noncancerous tissues and the relationship with the prognosis of the patients; 2. the study of RNF2 against the liver The effect of cancer cells; 3. the interaction between RNF2 and MANF was demonstrated. Methods: in SMMC-7721 and TEL-7402 cells, the effects of RNF2 on the proliferation and apoptosis of hepatoma cells were proved by MTT experiment, flow cytometry and Western blot detection of Caspase-3, and the study was conducted by flat test, soft cloned agar experiment, scratch test, Transwell experiment and so on. The inhibitory effect of RNF2 on hepatoma cells; using cell immunofluorescence, tissue immunofluorescence, and tissue immunoprecipitation to verify the interaction of RNF2 and MANF in HCC; tunicamycin (TM) and oxygen glucose deprivation (OGD) were used to treat SMMC-7721 and TEL-7402 cells respectively. After overexpression of RNF2, RT-PCR and Western blot were used to detect the gene and protein expression of MANF; RNF2-myc plasmids were transfected in SMMC-7721 cells (0 mu g, 0.25 micron, 0.5 mu g, 1 mu g). The expression of egg white was detected by immunoblotting with TM and immunoblotting. The expression of RNF2 in 150 cases of hepatocellular carcinoma and 136 cases of non tumor control liver tissue was detected by immunohistochemistry. The results showed that RNF2 was expressed in all cases, and compared with non cancer control, the ratio of high expression of RNF2 in the liver tissue of hepatocellular carcinoma patients decreased significantly (P0.01).2. RNF2 could increase the death of hepatoma cells after OGD treatment and transfect RNF2 over expression plasmid and Si RNA in SMMC-7721 cells. After OGD treatment of 2.5 h, it was stained with PI to count the red PI positive cells in the visual field, and the statistical analysis was carried out. The result was that after the expression RNF2, the death cells were increased. After the silence of RNF2, the death cell decreased, suggesting that RNF2 may promote the death of hepatoma cells in the absence of glucose deprivation.3.RNF2 and promote the transfection of RNF2-si RNA plasmid in SMMC-7721 cell apoptosis SMMC-7721 cells and undergo OGD treatment. Then the cell apoptosis is detected by flow cytometry, and caspase-3 is detected by immunoblotting technique. Results RNF2 could promote the apoptosis of OGD induced cells and the expression of Caspase-3. The effect of.4.RNF2 on the malignant behavior of HCC cells 4.1 RNF2 inhibited the proliferation of liver cancer cells in SMMC-7721 and TEL-7402 cells, and the RNF2-siRNA and RNF-myc plasmids were transfected respectively in SMMC-7721 and TEL-7402 cells, and the OD values of each group were detected by MTT method and clone formation test. The ability of single cell clone formation was found. The proliferation ability of cells increased after RNF2 silencing, and overexpression of RNF2 made the proliferation ability of cells weakened. The cell viability was also detected by flow cytometry, and the proliferation ability of cells increased by.4.2 RNF2 to inhibit the migration of liver cancer cells by scratch test. The migration ability of RNF2-si RNA and RNF2-myc plasmids was not transfected. The results showed that after the silence of RNF2, the migration ability of the cells was enhanced and the overexpression of RNF2 reduced the migration ability of the cells. The results suggested that RNF2 had inhibitory effect on the migration of hepatoma cells by the inhibition of.4.3 RNF2 on the invasion ability of hepatoma cells. In the SMMC-7721 and TEL-7402 cells expressing RNF2, the cell invasiveness was detected by Transwell assay. The results showed that the number of cells passing through the T4 cell in the silent RNF2 cell group was more than that of the transfected vector control; on the contrary, the overexpression of RNF2 could inhibit the migration of cells, suggesting that RNF2 could inhibit the liver cancer cells. The expression of RNF2 and MANF was observed by immunofluorescence double labeled.5.RNF2 and MANF in the cell nuclei of the cell nuclei of the SMMC-7721 nuclei after TM treatment 6 h or OGD treated with 2.5 h. The expression of RNF2 and MANF in the tissues was detected by double immunofluorescence method after the liver tissue was embedded in the liver cancer patients. The results showed that the co localization of both.7.RNF2 and MANF in liver tissues was also found to be the interaction of RNF2 and MANF in the liver tissues. We used the liver cancer tissue to lapping and extracting the protein in the immunoprecipitation experiment. The RNF2 protein in the tissue was precipitated with RNF2 antibody and the MANF in the immune precipitates was detected by IB. Meanwhile, the MANF antibody co precipitated RNF2. results suggested that RNF2 can interact with MANF in the liver cancer tissues without affecting the transcription of the MANF gene. SMMC-7721 cells were silent RNF2 or transfected with RNF2 plasmids, and the expression level of MANF gene was detected by RT-PCR method. The results showed that the m RNA level of MANF was almost unchanged in the cells of the silent RNF2 or over the expression of RNF2, and the level of the MANF protein was influenced by the instantaneous transfection. RNF2-si RNA or RNF2-myc plasmids were used to detect the protein expression level of MANF by immunoblotting. The results showed that the expression of MANF was downregulated after the silence of RNF2, and the expression of MANF was up-regulated after overexpressing RNF2, and the expression level of MANF was detected by cell immunofluorescence, and the MANF expression was found in the RNF2 that was silenced, while RNF2 was in RNF2. In the overexpressed cells, the expression of MANF also up-regulated the protein level of.10.RNF2 dose-dependent regulating MANF in SMMC-7721 cells transfected to RNF2-myc plasmid 0 mu g, 0.25 g, 0.5 mu g, 1 u g, and divided into control group, TM stimulation group (6 h), OGD stimulus group (2.5), and detected the protein expression by immunoblotting method. The results found that the protein expression was detected by immunoblotting. The protein level of MANF increased gradually with the gradual increase of RNF2-myc transfection dose. It suggests that MANF has a dose dependence on RNF2 at the protein level. Conclusion: 1.RNF2 promotes the apoptosis of hepatoma cells; 2.RNF2 inhibits HCC; 3.RNF2 and MANF have interaction in HCC; 4.RNF2 does not affect the transcription of the MANF genes, but can be dose-dependent. The protein level of MANF was up-regulated.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R735.7

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7 楊秉輝;;肝癌綜合治療的選擇[A];第三屆中國(guó)腫瘤學(xué)術(shù)大會(huì)教育論文集[C];2004年

8 談菊萍;;肝癌病人的心理表現(xiàn)及護(hù)理對(duì)策[A];全國(guó)腫瘤護(hù)理學(xué)術(shù)交流暨專題講座會(huì)議論文匯編[C];2005年

9 曾帶娣;岳建榮;王翠霞;田月月;;肝癌病人心理變化的護(hù)理對(duì)策[A];全國(guó)傳染病護(hù)理學(xué)術(shù)交流暨專題講座會(huì)議論文匯編[C];2006年

10 林云萍;;肝癌病人的心理特點(diǎn)及護(hù)理對(duì)策[A];全國(guó)腫瘤護(hù)理學(xué)術(shù)交流暨專題講座會(huì)議論文匯編[C];2008年

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