本文選題：STAT3 + RNA干擾　； 參考：《山東大學(xué)》2015年博士論文

【摘要】：原發(fā)性肝細(xì)胞癌(Hepatocelluar Carcinoma, HCC)是嚴(yán)重?fù)p害全球人類生命健康的消化系統(tǒng)惡性腫瘤,發(fā)病率居所有惡性腫瘤中第6位,死亡率居第3位,每年死亡人數(shù)基本等于新發(fā)病數(shù),并呈現(xiàn)逐年增加的趨勢,專家們預(yù)計2015年——20年達(dá)到疾病平臺期。肝細(xì)胞癌的發(fā)生是多步驟,多基因作用的結(jié)果。肝細(xì)胞癌的主要危險因素包括感染HBV或HCV、酒精性肝病和非酒精性血液系統(tǒng)疾病,并與地理區(qū)域以及種族或民族有關(guān)。HCC早期無明顯癥狀,轉(zhuǎn)移早,發(fā)現(xiàn)晚,惡性程度高,能夠手術(shù)切除的患者較少,預(yù)后差,即使手術(shù)治療,大多數(shù)患者術(shù)后2年復(fù)發(fā)率和5年復(fù)發(fā)率分別為50%和75%。目前,肝細(xì)胞癌的診斷和治療手段得到了不斷提升,首選方濾還是以手術(shù)為主的綜合治療,但肝細(xì)胞癌患者的預(yù)后仍不理想。因此,深入研究及了解肝細(xì)胞癌的發(fā)生發(fā)展作用機制,才能早期診斷,早期治療,提高患者的生存期和生活質(zhì)量。研究表明原發(fā)性肝細(xì)胞癌發(fā)生、發(fā)展與多種信轉(zhuǎn)導(dǎo)通路的異常激活或者異常沉默有著密切聯(lián)系。JAK/STAT3言號轉(zhuǎn)導(dǎo)途徑介導(dǎo)腫瘤細(xì)胞與基質(zhì)或免疫細(xì)胞之間的聯(lián)絡(luò),調(diào)控和誘導(dǎo)與腫瘤細(xì)胞增殖、分化、凋亡密切相關(guān)的基因異常表達(dá),促進腫瘤細(xì)胞增殖、惡性轉(zhuǎn)化、阻礙凋亡。JAK和STAT3是許多細(xì)胞因子受體系統(tǒng)的關(guān)鍵分子,STAT3通過多肽類配體與它們的受體相結(jié)合而被激活,同時也可以被細(xì)胞內(nèi)的激酶激活,進而介導(dǎo)細(xì)胞激酶,生長因子和激素等信號轉(zhuǎn)導(dǎo)至細(xì)胞核,參加細(xì)胞生長、新陳代謝、分化、生存、抑制細(xì)胞凋亡和抵抗外源性病原體。細(xì)胞因子等配體與受體結(jié)合后,gp130 (CDw13,免疫球蛋白超家族IGSF成員)趨附于受體分子LIFR,并相結(jié)合形成二聚體,JAK分別與LIFR和gp130相結(jié)合,激活相應(yīng)的JAK,活化的JAK自身磷酸化,并進一步磷酸化LIFR和gp130, gp130和LIFR磷酸化位點作為STAT3的SH2區(qū)錨鏈位點,當(dāng)然STAT3的SH2區(qū)錨鏈位點也可以與其他受體結(jié)合,激活其他信號轉(zhuǎn)導(dǎo)途徑,如MAPK、PI3K/Akt信號轉(zhuǎn)導(dǎo)途徑�；罨腟TAT3與受體分離,兩個STAT3分子間通過SH2區(qū)相連接形成形成二聚體,隨后穿行核孔,進入細(xì)胞核,STAT3分子與DNA相應(yīng)區(qū)域結(jié)合,誘導(dǎo)血管生成相關(guān)基因,細(xì)胞周期調(diào)控基因及抗凋亡基因等基因表達(dá)。研究表明,如果STAT3發(fā)生異常激活就會導(dǎo)致細(xì)胞的異常增殖、惡性轉(zhuǎn)化、調(diào)亡抑制以及免疫抑制。多中心研究顯示,肝細(xì)胞癌等惡性腫瘤細(xì)胞中JAK/STAT3信號轉(zhuǎn)導(dǎo)途徑持續(xù)性激活及STAT3過表達(dá),磷酸化STAT3在肝細(xì)胞癌等惡性腫瘤中高表達(dá)�；罨腟TAT3促進肝細(xì)胞癌的發(fā)生,提高肝癌細(xì)胞再生能力和侵襲性。腫瘤的生長依賴血管的生成,通過新生血管給腫瘤細(xì)胞提供豐富的養(yǎng)料與氧分,JAK/STAT3信號轉(zhuǎn)導(dǎo)途徑調(diào)節(jié)VEGFR-2的表達(dá),是腫瘤血管新生和腫瘤細(xì)胞轉(zhuǎn)移的主要因子。STAT3是影響腫瘤細(xì)胞免疫反應(yīng)的一個重要分子,控制腫瘤細(xì)胞分泌細(xì)胞因子來調(diào)節(jié)免疫反應(yīng),造成腫瘤細(xì)胞免疫逃逸。RNAi (RNA interference)——RNA干擾,是指一系列非編碼RNA,由21-23 bp長的雙鏈RNA分子介導(dǎo),誘發(fā)同源mRNA降解的轉(zhuǎn)錄后基因沉默(PTGS)機制。研究人員設(shè)計目標(biāo)內(nèi)源性mRNA,合成siRNA,核糖核酸內(nèi)切酶制備siRNA或siRNA的前體(如短發(fā)夾RNA (shRNA)或長的雙鏈RNA (dsRNA),將其倒入細(xì)胞內(nèi)甚至整個器官內(nèi),高通量將基因沉默,對經(jīng)典基因研究和治療方式產(chǎn)生了挑戰(zhàn)。RNAi是一種轉(zhuǎn)錄后基因沉默(PTGS)小分子調(diào)控RNA,包括小NA (miRNA, microRNA)和小干擾RNA (siRNA, small interfering RNA),是保護不受外部基因甚至內(nèi)部基因侵?jǐn)_,控制細(xì)胞生長,調(diào)控基因表達(dá),生物體適應(yīng)外界環(huán)境的重要機制,是一種比較早期的動植物,甚至微生物等生命體就已經(jīng)具有的生物途徑。作為轉(zhuǎn)錄后基因沉默(PTGS)機制的特殊性,RNAi已經(jīng)成為腫瘤學(xué)基礎(chǔ)及臨床研究的一種工具。轉(zhuǎn)錄因子將細(xì)胞外信號轉(zhuǎn)導(dǎo)入基因組中,是腫瘤發(fā)生、發(fā)展的關(guān)鍵因素,阻斷轉(zhuǎn)錄因子是目前惡性腫瘤治療的有效方法,針對腫瘤的靶向治療的研究,在不同水平中斷腫瘤細(xì)胞中STAT3信號通路,阻斷轉(zhuǎn)錄因子STAT3的表達(dá),誘導(dǎo)腫瘤細(xì)胞的凋亡。RNA干涉技術(shù)靶向阻斷STAT3基因具有高效、特異、操作簡便、低毒等特點。為研究JAK/STAT3信號轉(zhuǎn)導(dǎo)途徑對肝癌細(xì)胞凋亡的影響,本實驗擬通過RNA干擾(RNA interference, RNAi)沉默BEL-7402肝癌細(xì)胞STAT3基因。該研究可能為靶向腫瘤基因治療提供實驗依據(jù)。首先構(gòu)建靶向STAT3的RNA干擾載體,應(yīng)用脂質(zhì)體LipofectamineTM 2000將前期構(gòu)建的pGC-STAT3-siRNA質(zhì)粒轉(zhuǎn)染至BEL-7402肝癌細(xì)胞,并檢測其基因沉默效應(yīng),根據(jù)實驗分為對照組、陰性質(zhì)粒組、STAT3-siRNA組,分別通過分別通過流式細(xì)胞術(shù),檢測細(xì)胞凋亡比率的變化,JC-1熒光染色觀察線粒體膜電勢△甲m變化,并利用Western Blot方法檢測Caspase 3蛋白質(zhì)水平的變化。JAK/STAT3信號轉(zhuǎn)導(dǎo)途徑與肝細(xì)胞癌有關(guān)聯(lián),通過流式細(xì)胞術(shù)檢測結(jié)果顯示,對照組,陰性質(zhì)粒組及STAT3-siRNA)貢粒組凋亡率分別為9.26±0.42%,17.53±0.98%及45.24±0.79%,經(jīng)統(tǒng)計學(xué)分析,STAT3-siRNA組細(xì)胞凋亡率明顯高于對照組和陰性質(zhì)粒組(P0.05),靶向STAT3促進BEL-7402細(xì)胞凋亡。凋亡(apoptosis)是細(xì)胞在多種因素作用下,通過基因調(diào)控而發(fā)生的一系列程序化細(xì)胞死亡想象,普遍存在于生物界。細(xì)胞凋亡早期核酸酶的激活及磷酯酰絲氨酸的膜暴露晚于線粒體膜電位△Ψm下降,本實驗檢測各組細(xì)胞△Ψm的數(shù)值變化結(jié)果顯示：實驗組細(xì)胞紅色熒光減弱,綠色熒光增強,線粒體膜電位△Ψm降低(58.87±1.90%,P0.05),對照組及陰性質(zhì)粒組細(xì)胞綠色熒光相對較弱,紅色熒光較強,線粒體膜電位△Ψm較高(90.73±1.75%,90.03±1.68%,P0.05),說明靶向STAT顯著降低BEL-7402肝癌細(xì)胞線△Ψm,引起線粒體膜去極化作用。1994年caspase-3基因被Fernandez-Alnemri從數(shù)據(jù)庫篩選、克隆,1996年將其編碼的這種蛋白酶命名為caspase-3,目前已經(jīng)獲得caspase-3的X線結(jié)晶圖像。caspase-3是細(xì)胞凋亡過程中最主要的終末剪切酶,在細(xì)胞凋亡中起著不可替代的作用。凋亡途徑最終啟動,caspase-3被降解為分子量為P17/19的acti ved-caspase-3至關(guān)重要,細(xì)胞核中的多聚ADP-核糖聚合酶(PARP,116kD)被活性caspase-3剪切,使其不能與DNA有效結(jié)合,導(dǎo)致Ca2+/Mg2+依賴性內(nèi)切核酸酶的活性增高,進而裂解核小體間的DNA,引起細(xì)胞凋亡。Western Blotting結(jié)果顯示actived-caspase3蛋白(17/19 kDa)在實驗組表達(dá)明顯高于對照組和陰性質(zhì)粒組(0.48±0.05 vs.0.22±0.04和0.26±0.06,P0.05),Caspase 3(35kDa)表達(dá)各組無明顯差異(P0.01)(圖4)。提示siRNA-STAT3冗默STAT3基因可明顯降低細(xì)胞線粒體△Ψm,激活caspase-3增強,促進肝癌細(xì)胞凋亡、壞死。Bcl-2家族是調(diào)節(jié)線粒體通透性的主要成分,與細(xì)胞死亡信號相連接,對細(xì)胞的死亡起決定作用。本實驗通過siRNA-STAT3沉默STAT3基因,阻斷JAK/STAT3信號轉(zhuǎn)導(dǎo)途徑,阻斷Bcl-2基因轉(zhuǎn)錄,Bcl-2表達(dá)水平下降,Bcl-2同源二聚體形成受到抑制,Bax就不能與Bcl-2相結(jié)合,那么Bax就會大量在線粒體膜上形成二聚體,導(dǎo)致線粒體膜電勢能下降,激活caspase家族一系列蛋白分子,引起凋亡級聯(lián)反應(yīng),促進Bel-7402肝癌細(xì)胞凋亡�？傊�,通過RNAi沉默BEL-7402肝癌細(xì)胞STAT3基因,從翻譯水平阻抑STAT3基因表達(dá),來抑制JAK/STAT3信號轉(zhuǎn)導(dǎo)途徑,增加了肝癌細(xì)胞的凋亡率,表現(xiàn)出更強大而且穩(wěn)定的促凋亡作用,為肝癌細(xì)胞的信號轉(zhuǎn)導(dǎo)途徑靶向治療的優(yōu)化提供了體外實驗數(shù)據(jù)。
[Abstract]:Hepatocelluar Carcinoma (HCC) is the digestive system malignant tumor that seriously damages human life and health in the world. The incidence of the disease ranks sixth in all malignant tumors. The mortality rate is third. The annual death toll is basically equal to the number of new diseases, and the trend is increasing year by year. Experts expect to reach the disease in 2015 - 20 years. Stage. The occurrence of hepatocellular carcinoma is the result of multistep, multi gene action. The main risk factors for hepatocellular carcinoma include infection of HBV or HCV, alcoholic liver disease, and non-alcoholic blood system diseases, which have no obvious symptoms in the early stages of.HCC, as well as in geographical areas and ethnic or ethnic groups, early detection, high malignancy, and surgical excision. There were fewer patients and poor prognosis. The 2 year recurrence rate and 5 year recurrence rate of most patients were 50% and 75%., respectively, and the diagnosis and treatment of hepatocellular carcinoma were improved continuously. The first choice of formula filter or operation based comprehensive treatment, but the prognosis of the patients with hepatocellular carcinoma was still not ideal. Therefore, in-depth study and understanding of the prognosis of hepatocellular carcinoma patients are still not ideal. The development and development of hepatocellular carcinoma can be used for early diagnosis, early treatment, and improvement of life and quality of life. Studies have shown that the development of primary hepatocellular carcinoma is closely related to the abnormal activation or abnormal silence of a variety of signal transduction pathways that mediate tumor cells and matrix or immunization with.JAK/STAT3 transduction pathway. Communication between cells, regulating and inducing abnormal expression of genes closely related to proliferation, differentiation and apoptosis of tumor cells, promoting tumor cell proliferation, malignant transformation, blocking apoptotic.JAK and STAT3 are key molecules of many cytokine receptor systems, STAT3 is activated by the combination of peptide complexes and their receptors, and can also be used. Activated by kinases in cells, and then mediate the signal transduction of kinases, growth factors and hormones to the nucleus, and participate in cell growth, metabolism, differentiation, survival, inhibition of apoptosis and resistance to exogenous pathogens. After the binding of ligand to the receptor, gp130 (CDw13, IGSF members of the immunoglobulin superfamily) are attached to the receptor. Molecular LIFR, combined with the formation of two polymer, combined with LIFR and gp130, activates the corresponding JAK, activated JAK itself phosphorylation, and further phosphorylation of LIFR and gp130, gp130 and LIFR phosphorylation sites as STAT3 SH2 region anchor sites, and of course the binding site can also be combined with other receptors to activate other signals. Guided pathways, such as MAPK, PI3K/Akt signal transduction pathway, activated STAT3 and receptor isolation, two STAT3 molecules are formed through SH2 region to form two polymers, then pass through nuclear pores and enter the nucleus, STAT3 molecules combine with the corresponding region of DNA to induce angiogenesis related genes, cell cycle regulation gene and anti apoptotic gene expression. Studies have shown that abnormal activation of STAT3 leads to abnormal proliferation of cells, malignant transformation, suppression of apoptosis and immunosuppression. Multicenter studies show that JAK/STAT3 signal transduction pathway is persistent and STAT3 overexpression in malignant tumor cells such as hepatocellular carcinoma, and phosphorylated STAT3 is highly expressed in malignant tumors such as hepatocellular carcinoma. STAT3 promotes the development of hepatocellular carcinoma and improves the regeneration ability and invasiveness of hepatoma cells. The growth of the tumor depends on the formation of blood vessels and provides rich nutrients and oxygen in the tumor cells through the neovascularization. The JAK/STAT3 signal transduction pathway regulates the expression of VEGFR-2, which is the main factor of tumor blood tube neoplasm and tumor cell metastasis,.STAT3 An important molecule that affects the immune response of a tumor cell, controls the secretion of cytokines by the tumor cells to regulate the immune response and causes the immune escape of the tumor cells,.RNAi (RNA interference) - RNA interference. It refers to a series of non coded RNA, mediated by 21-23 BP long double stranded RNA molecules, and induces the post transcriptional gene silencing (PTGS) of the degradation of homologous mRNA. Mechanism. Researchers designed target endogenous mRNA, synthesized siRNA, ribonucleic acid endonuclease to prepare precursors of siRNA or siRNA (such as short hairpin RNA (shRNA) or long double stranded RNA (dsRNA), and pour it into cells and even the whole organ. High throughput can silence the gene, and the challenge of classical gene research and treatment is a transcription. Gene silencing (PTGS) small molecules regulate RNA, including small NA (miRNA, microRNA) and small interference RNA (siRNA, small interfering RNA). It is an important mechanism to protect the growth of cells, regulate gene expression, and adapt to the environment of the outside world. It is a kind of early animal and plant, or even microorganism, and so on. The biological pathway that the life body has already has. As a special mechanism of post transcriptional gene silencing (PTGS), RNAi has become a tool for the basis of oncology and clinical research. The transcription factors transfer the extracellular signal into the genome, which is the key factor for the development of tumor, and blocking the transcription factors is effective for the treatment of malignant tumors. Methods, aiming at the target therapy of tumor, the STAT3 signaling pathway in tumor cells was interrupted at different levels and the expression of transcription factor STAT3 was blocked. The apoptosis.RNA interference technique of tumor cells was induced to target the STAT3 gene with high efficiency, specificity, simple operation, low toxicity and so on. To study the JAK/STAT3 signal transduction pathway for hepatoma cells The effect of apoptosis, this experiment is to silence the STAT3 gene of BEL-7402 hepatoma cells by RNA interference (RNA interference, RNAi). This study may provide experimental basis for targeting tumor gene therapy. Firstly, construct RNA interference vector of targeted STAT3, and transfect the early constructed pGC-STAT3-siRNA plasmid to BEL-7402 by liposome LipofectamineTM 2000. The gene silencing effect of hepatoma cells was detected. According to the experiment, the cells were divided into control group, negative plasmid group and STAT3-siRNA group. By flow cytometry, the changes of apoptosis ratio were detected by flow cytometry, JC-1 fluorescence staining was used to observe the changes of mitochondrial membrane potential delta m, and the Western Blot method was used to detect the change of Caspase 3 protein level.J The AK/STAT3 signal transduction pathway was associated with hepatocellular carcinoma. By flow cytometry, the apoptosis rate of the control group, negative plasmid group and STAT3-siRNA) was 9.26 + 0.42%, 17.53 + 0.98% and 45.24 + 0.79% respectively. By statistical analysis, the cell withering rate of the STAT3-siRNA group was significantly higher than that of the control group and the negative plasmid group (P0.05). STAT3 promotes apoptosis of BEL-7402 cells. Apoptosis (apoptosis) is a series of programmed cell death imaginations that occur through gene regulation and regulation by a variety of factors. The activation of nuclease in the early stage of apoptosis and the membrane exposure of phosphonyl serine later than the mitochondrial membrane potential delta m decreased. The results of the numerical change of the group cell delta m showed that the red fluorescence of the experimental group was weakened, the green fluorescence enhanced, the mitochondrial membrane potential delta m decreased (58.87 + 1.90%, P0.05), the green fluorescence of the control group and the negative plasmid group was relatively weak, the red fluorescence was stronger and the mitochondrial membrane potential delta m was higher (90.73 + 1.75%, 90.03 + 1.68%, P0.05), indicating the target. STAT significantly reduced BEL-7402 hepatoma cell line delta m, causing mitochondrial membrane depolarization, caspase-3 gene was screened by Fernandez-Alnemri from database and cloned by Fernandez-Alnemri in 1996. In 1996, the protease was named caspase-3. At present, the X-ray crystallized.Caspase-3 of Caspase-3 is the most important in the process of cell apoptosis. Terminal shear enzyme plays an irreplaceable role in cell apoptosis. Apoptosis pathway eventually starts, and caspase-3 is degraded to acti ved-caspase-3 with molecular weight P17/19, and the poly ADP- ribose polymerase (PARP, 116kD) in the nucleus is cut by active Caspase-3, so that it can not be effectively combined with DNA, resulting in Ca2+/Mg2+ dependence. The activity of nuclease increased and then cleavage of DNA between the nucleosomes, causing apoptosis.Western Blotting results showed that the expression of actived-caspase3 protein (17/19 kDa) in the experimental group was significantly higher than that of the control group and negative plasmid group (0.48 + 0.05 vs.0.22 + 0.04 and 0.26 + 0.06, P0.05), Caspase 3 (35kDa) expressed no significant difference (P0.01) (Fig. 4). The siRNA-STAT3 redundant STAT3 gene can obviously reduce the mitochondrial delta m, activate caspase-3 and promote the apoptosis of the hepatoma cells. The necrotic.Bcl-2 family is the main component of the mitochondrial permeability, which is connected with the cell death signal, and plays a decisive role in the cell death. This experiment blocked the JAK/STAT by siRNA-STAT3 silencing the STAT3 gene and blocked JAK/STAT. 3 signal transduction pathway, blocking Bcl-2 gene transcription, Bcl-2 expression level decline, Bcl-2 homologous two polymer formation is inhibited, Bax can not be combined with Bcl-2, then Bax will form a large number of polymers on the mitochondrial membrane, leading to the decrease of the mitochondrial membrane potential energy, activating a series of protein molecules in the caspase family, causing apoptosis cascade reaction and promoting B. El-7402 hepatoma cell apoptosis. In a word, RNAi silencing the STAT3 gene of BEL-7402 hepatoma cells, inhibiting the expression of STAT3 gene from the translation level, inhibiting the JAK/STAT3 signal transduction pathway, increasing the apoptosis rate of the hepatoma cells, showing a stronger and stable apoptosis promoting effect, and optimizing the target therapy for the signal transduction pathway of the hepatoma cells. The experimental data were provided in vitro.
【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】：2015
【分類號】：R735.7

【共引文獻】

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