本文選題：惡性膠質(zhì)瘤 + RNF135基因　； 參考：《大連醫(yī)科大學(xué)》2015年博士論文

【摘要】：目的：探討RNF135基因與膠質(zhì)母細胞瘤發(fā)生、發(fā)展及預(yù)后的聯(lián)系,并通過體內(nèi)及體外實驗研究RNF135基因?qū)δz質(zhì)母細胞瘤細胞U87的增殖、遷移及細胞周期的影響以及RNF135基因?qū)87細胞作用的機制,為膠質(zhì)母細胞瘤提供新的基因治療靶點。方法：首先對28例膠質(zhì)瘤組織和12例正常的腦組織采用實時定量PCR與Western Blot實驗檢測組織中RNF135基因的表達差異。采用免疫組化實驗比較123例膠質(zhì)瘤和12例正常腦組織中RNF135蛋白的表達情況,(標(biāo)本來源2004年7月到2009年6月,在大連醫(yī)科大學(xué)附屬第一醫(yī)院手術(shù)的膠質(zhì)瘤患者,正常腦組織為外傷、腦出血手術(shù)患者術(shù)區(qū)周邊非功能區(qū)腦組織,所有標(biāo)本獲得都經(jīng)過大連醫(yī)科大學(xué)附屬第一醫(yī)院醫(yī)學(xué)倫理委員會批準(zhǔn)),用統(tǒng)計學(xué)分析RNF135基因表達與患者年齡、性別、膠質(zhì)瘤病理組織類型、預(yù)后及生存時間是否有相關(guān)性。然后通過構(gòu)建shRNF135穩(wěn)轉(zhuǎn)的U87膠質(zhì)母細胞瘤細胞系,研究RNF135基因?qū)δz質(zhì)母細胞瘤細胞U87增殖、遷移及細胞周期的影響及機制。通過使用慢病毒包裝shRNA轉(zhuǎn)染U87細胞對RNF135基因進行沉默,在體外建立穩(wěn)定低表達RNF135基因的U87細胞系,同時通過慢病毒包裝LVTHMGFP轉(zhuǎn)染U87細胞作為對照組,慢病毒轉(zhuǎn)完后通過流式細胞術(shù)篩選轉(zhuǎn)染成功的細胞繼續(xù)培養(yǎng),培養(yǎng)的細胞用實時定量PCR與Western Blot實驗驗證RNF135基因的表達以確定穩(wěn)定低表達RNF135基因的U87細胞系模型建立成功。實時定量PCR與Western Blot實驗驗證成功后首先檢測干擾RNF135基因表達對U87細胞增殖的影響,細胞活性用MTT實驗檢測,通過劃痕實驗與Boyden小室遷移實驗驗證干擾RNF135表達后U87細胞遷移能力的變化情況。利用Western Blot實驗驗證RNF135基因與細胞通路p38及ERK之間的關(guān)系,利用細胞周期實驗解釋RNF135低表達對細胞周期的影響,通過Western Blot實驗檢測細胞周期相關(guān)蛋白的表達情況。最后通過荷瘤裸鼠模型在體內(nèi)驗證干擾RNF135基因表達對U87細胞在裸鼠體內(nèi)成瘤的影響。結(jié)果：臨床病例的統(tǒng)計分析表明RNF135基因與膠質(zhì)瘤患者預(yù)后及生存時間均有明顯的相關(guān)性。在所有調(diào)查的123例膠質(zhì)瘤患者當(dāng)中,RNF135基因明顯高表達。在小于50歲的63名膠質(zhì)瘤患者中RNF135基因高表達的概率為69.8%略微低于50歲以上的60名患者中RNF135基因高表達的概率(70%)。在73名女性膠質(zhì)瘤患者中RNF135基因高表達的概率為74%,而在50名男性膠質(zhì)瘤患者中RNF135基因高表達的概率為63%,女性患者的概率略微高于男性患者的概率。在9名少突膠質(zhì)瘤患者中RNF135基因高表達的概率為77.8%,在60名間變性星型細胞瘤患者中RNF135基因高表達的概率為60%而在40名膠質(zhì)母細胞瘤的患者中RNF135基因高表達的概率也為60%。按世界衛(wèi)生組織對膠質(zhì)瘤惡性程度的分類來看,惡性程度越高的膠質(zhì)瘤中RNF135基因高表達的概率越高。Ⅲ和Ⅳ級的惡性膠質(zhì)瘤患者的RNF135基因高表達的概率78%明顯高于Ⅰ和Ⅱ級的惡性膠質(zhì)瘤患者中RNF135基因高表達的概率34.8%。甚至Ⅰ和Ⅱ級的惡性膠質(zhì)瘤患者中RNF135基因低表達的概率為65.2%,遠高于RNF135基因高表達的概率22%。經(jīng)SPSS統(tǒng)計分析發(fā)現(xiàn),膠質(zhì)瘤中RNF135的表達情況與患者性別、年齡、病理類型沒有相關(guān)性,P值分別為0.985、0.236和0.766。WHO膠質(zhì)瘤病理分級中,Ⅱ和Ⅳ級病理中的RNF135表達較I和II級的高,經(jīng)統(tǒng)計學(xué)分析,p0.05。綜合以上實驗結(jié)果可知,膠質(zhì)瘤的惡性程度與RNF135的異常表達情況相關(guān)。高惡性程度的膠質(zhì)瘤更容易發(fā)生RNF135基因的高表達。而Ⅲ和Ⅳ級的惡性膠質(zhì)瘤,尤其是Ⅳ級惡性膠質(zhì)瘤(多形性膠質(zhì)母細胞瘤)往往預(yù)后很差而且患者生存時間很短。因此RNF135基因與膠質(zhì)瘤的發(fā)生與預(yù)后均有密切的聯(lián)系。同樣的,在體外實驗中我們發(fā)現(xiàn)RNF135基因在膠質(zhì)瘤組織中的表達明顯高于正常腦組織。我們用Western blot方法,分析在28個膠質(zhì)瘤樣本中RNF135蛋白表達量,明顯高于正常的腦組織樣本中RNF135蛋白表達量。以上結(jié)果說明膠質(zhì)瘤細胞尤其是Ⅲ和Ⅳ級的惡性膠質(zhì)瘤細胞往往發(fā)生RNF135基因程高表達。這種高表達不僅表現(xiàn)在RNF135基因的mRNA水平,而且蛋白水平也表現(xiàn)出一致的結(jié)果。在用慢病毒轉(zhuǎn)染shRNA干擾RNF135基因在U87細胞中的表達后,實時定量PCR顯示RNF135基因的mRNA表達水平及Western Blot實驗顯示RNF135基因的蛋白較空載對照組的明顯降低,p0.05統(tǒng)計學(xué)有意義。以上的實時定量PCR結(jié)果與Western Blot實驗表明穩(wěn)定低表達RNF135基因的U87細胞系建立成功。RNF135基因被干擾后U87細胞的增殖速度明顯低于對照組,這說明高表達的RNF135基因有助于U87細胞的增殖。而劃痕實驗與Boyden小室遷移實驗同時顯示RNF135基因被干擾后U87細胞的遷移速度明顯低于對照組,這說明高表達的RNF135基因有助于U87細胞的遷移。Western Blot實驗顯示穩(wěn)定低表達RNF135基因的U87細胞中的Erkl/2及P-Erkl/2的表達量顯著降低而p38及P-p38的表達量沒有明顯變化,這說明干擾RNF135基因后對U87細胞產(chǎn)生的抑制功能很可能是通過抑制ERK的磷酸化來實現(xiàn)的。細胞周期實驗表明干擾RNF135基因會引起U87細胞阻滯在G0/G1期,這說明干擾RNF135基因是通過阻滯細胞周期從而抑制細胞增殖。而對細胞周期相關(guān)蛋白的Western Blot實驗的結(jié)果顯示,干擾RNF135基因后細胞細胞周期蛋白依賴性激酶CDK4的表達降低,而細胞周期抑制蛋白p27和p21的表達增多從而導(dǎo)致細胞周期阻滯在G0/GI期。荷瘤裸鼠實驗中穩(wěn)定低表達RNF135基因的U87細胞所成的瘤塊明顯小于對照組。說明干擾RNF135基因在裸鼠體內(nèi)抑制U87細胞的增殖。結(jié)論：RNF135基因與膠質(zhì)瘤的發(fā)生與預(yù)后均有密切的聯(lián)系,干擾RNF135基因可以使U87細胞阻滯在G0/G1期從而抑制細胞增殖及細胞的遷移能力。干擾RNF135基因后對U87細胞產(chǎn)生的抑制作用很可能是通過抑制ERK的磷酸化實現(xiàn)的,干擾RNF135基因通過抑制細胞周期蛋白依賴性激酶CDK4并上調(diào)細胞周期抑制蛋白p27和p21的表達從而導(dǎo)致細胞周期阻滯在G0/G1期,以上的研究表明RNF135基因有望作為治療膠質(zhì)母細胞瘤的新靶點。
[Abstract]:Objective: To investigate the relationship between the RNF135 gene and the occurrence, development and prognosis of glioblastoma, and to study the effect of RNF135 gene on the proliferation, migration and cell cycle of glioblastoma cell U87 and the mechanism of RNF135 gene on U87 cells in vivo and in vitro, and provide new target for gene therapy for glioblastoma. Methods: the expression of RNF135 gene in the tissues of 28 glioma and 12 normal brain tissues was measured by real-time quantitative PCR and Western Blot. The expression of RNF135 protein in 123 gliomas and 12 normal brain tissues was compared by immunohistochemistry. (the source from July 2004 to June 2009, in Dalian medicine. The patients with glioma surgery in the first hospital affiliated to the University, the normal brain tissue for trauma, the peripheral nonfunctional brain tissue around the operation area of the patients with cerebral hemorrhage, all the specimens were approved by the medical ethics committee of the First Affiliated Hospital of Dalian Medical University. The RNF135 gene expression was statistically analyzed with the patient's age, sex, glioma pathology group. The effect and mechanism of the RNF135 gene on the proliferation, migration and cell cycle of glioblastoma cells by the construction of a shRNF135 stable U87 glioblastoma cell line. The RNF135 gene was silenced by transfecting U87 cells with the lentivirus package shRNA, and the construction of the RNF135 gene was built in vitro. The U87 cell line with low expression of RNF135 gene was established, and U87 cells were transfected through the lentivirus package LVTHMGFP as the control group. After the lentivirus was completed, the transfected cells were screened by flow cytometry to continue to be cultured. The cultured cells used real-time quantitative PCR and Western Blot to verify the expression of RNF135 gene to determine the stable low expression of RNF. The U87 cell line model of the 135 gene was successfully established. The effect of interference RNF135 gene expression on the proliferation of U87 cells was first detected by real-time quantitative PCR and Western Blot experiments. The cell activity was tested by MTT test, and the migration ability of U87 cells after RNF135 expression was verified by scratch test and Boyden chamber migration experiment. Western Blot experiment was used to verify the relationship between RNF135 gene and cell pathway p38 and ERK, and the effect of RNF135 low expression on cell cycle was explained by cell cycle experiment. The expression of cell cycle related proteins was detected by Western Blot experiment. Finally, the interference of RNF135 gene expression to U87 was verified by the model of tumor bearing nude mice in vivo. Results: the statistical analysis of clinical cases showed that the RNF135 gene was significantly correlated with the prognosis and survival time of the patients with glioma. In all 123 patients with glioma, the RNF135 gene was highly expressed. The probability of high expression of RNF135 gene in 63 glioma patients less than 50 years old The probability of high expression of RNF135 gene (70%) in 60 patients younger than 50 years old (70%). The probability of high expression of RNF135 gene in 73 female glioma patients was 74%, while the probability of high expression of RNF135 gene in 50 male glioma patients was 63%, and the probability of female patients was slightly higher than that of male patients. In 9 oligodendrocytes, the probability of the high expression of RNF135 gene was slightly higher than that of the male patients. The probability of high expression of RNF135 gene in tumor patients was 77.8%. The probability of high expression of RNF135 gene was 60% in 60 anaplastic astrocytoma patients and the probability of high expression of RNF135 gene in 40 patients with glioblastoma was also based on the classification of the malignant degree of the glioma by WHO, the higher the malignancy of glioma The higher probability of high expression of RNF135 gene in the tumor was higher. The probability of high expression of RNF135 gene in patients with grade III and IV malignant gliomas was significantly higher than the probability of high expression of RNF135 gene in patients with grade I and II malignant gliomas. The probability of low expression of RNF135 gene in patients with grade I and grade II malignant gliomas was 65.2%, far higher than RNF1. The probability of high expression of 35 gene 22%. showed that there was no correlation between the expression of RNF135 in glioma and the sex, age and pathological type of the patients. The P value was 0.985,0.236 and 0.766.WHO glioma pathological classification, and the RNF135 expression in grade II and IV was higher than that of I and II. By statistical analysis, p0.05. integrated experiments. The results show that the malignant degree of glioma is related to the abnormal expression of RNF135. The high malignant glioma is more likely to have high expression of RNF135 gene. And grade III and IV malignant glioma, especially grade IV malignant glioma (pleomorphic glioblastoma) often have poor prognosis and the patient's survival time is very short. So RNF135 base There is a close relationship with the occurrence and prognosis of glioma. Similarly, we found that the expression of RNF135 gene in glioma tissue is obviously higher than that of normal brain tissue in vitro. We use Western blot method to analyze the expression of RNF135 protein in 28 glioma samples, which is significantly higher than that of the normal brain tissue samples of RNF135 protein. The above results indicate that glioma cells, especially grade III and grade IV malignant glioma cells often have high expression of RNF135 gene process. This high expression is not only shown in the mRNA level of the RNF135 gene but also in the protein level. After the expression of the RNF135 gene in the U87 cells by the lentivirus transfected to the RNF135 gene, Real-time quantitative PCR showed the mRNA expression level of RNF135 gene and Western Blot experiment showed that the protein of RNF135 gene was significantly lower than that of the empty control group, and P0.05 statistics was significant. The above real-time quantitative PCR results and Western Blot experiments showed that the U87 fine cell line of stable low expression RNF135 gene was established. The proliferation rate of the cells was significantly lower than that of the control group, which indicated that the high expression of RNF135 gene was helpful to the proliferation of U87 cells. The scratch test and the Boyden cell migration experiment showed that the migration speed of U87 cells was significantly lower than that of the control group after the RNF135 gene was disturbed, which indicated that the high expression of the RNF135 gene was helpful to the migration of.Western Bl in U87 cells. The OT experiment showed that the expression of Erkl/2 and P-Erkl/2 in U87 cells with stable low expression of RNF135 gene decreased significantly and the expression of p38 and P-p38 did not change significantly. This indicated that the inhibition of U87 cells after the interference of RNF135 gene was likely to be realized by inhibiting the phosphorylation of ERK. Cell cycle experiments showed that interference RNF135 base U87 cells are blocked at G0/G1 stage, which indicates that the interference of RNF135 gene is by blocking cell cycle to inhibit cell proliferation. The result of Western Blot experiment on cell cycle related proteins shows that the expression of cell cycle protein dependent kinase CDK4 in cell cell is reduced after the interference of RNF135 gene, and cell cycle inhibitor protein p27 and P The increased expression of 21 resulted in cell cycle arrest in G0/GI phase. In nude mice, the tumor blocks of U87 cells with low expression of RNF135 gene in nude mice were significantly smaller than those of the control group. It indicated that the interference of RNF135 gene in nude mice to inhibit the proliferation of U87 cells in nude mice. Conclusion: there is a close relationship between the occurrence and prognosis of the RNF135 gene and glioma, and the interference is closely related to the prognosis. RNF135 gene can inhibit U87 cells in G0/G1 phase and inhibit cell proliferation and cell migration. The inhibition effect on U87 cells after interference with RNF135 gene may be achieved by inhibiting the phosphorylation of ERK, interfering with the RNF135 gene by inhibiting the cyclin dependent kinase CDK4 and up regulation of the cell cycle inhibitor protein. The expression of p27 and p21 leads to cell cycle arrest in G0/G1 phase. The above studies suggest that RNF135 gene is expected to be a new target for the treatment of glioblastoma.

【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R739.4

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