【摘要】：背景:腦膠質(zhì)瘤是腦中最常見(jiàn)的惡性腫瘤,具有快速浸潤(rùn)性生長(zhǎng)和術(shù)后高復(fù)發(fā)率的特點(diǎn)。低級(jí)別膠質(zhì)瘤患者(世界衛(wèi)生組織WHO I級(jí)和II級(jí))的5年生存率約為30%至70%,而高級(jí)別膠質(zhì)母細(xì)胞瘤(IV級(jí))的中位生存期為9至12個(gè)月。因此,有必要確定這種惡性疾病更多的生物標(biāo)志物和潛在的治療靶點(diǎn)。微小RNA(microRNA,miRNA)涉及一系列重要的生物過(guò)程,如細(xì)胞發(fā)育,分化,凋亡和增殖。異常mi RNA表達(dá)與各種腫瘤的發(fā)生和進(jìn)展相關(guān)。此外,表達(dá)失調(diào)的mi RNA可作為診斷和評(píng)估預(yù)后的生物標(biāo)志物。目的:研究miRNA在不同級(jí)別膠質(zhì)瘤中的差異表達(dá)情況,探討miRNA通過(guò)靶基因調(diào)控膠質(zhì)發(fā)生發(fā)展的分子機(jī)制。方法:(1)利用生物信息學(xué)對(duì)NCBI GEO數(shù)據(jù)庫(kù)內(nèi)膠質(zhì)瘤數(shù)據(jù)分析得出差異表達(dá)mi RNA,對(duì)22例膠質(zhì)瘤組織標(biāo)本通過(guò)PCR Array(內(nèi)含184miRNA引物預(yù)設(shè)計(jì)的PCR芯片)方法篩選膠質(zhì)瘤內(nèi)差異表達(dá)mi RNA,選取在膠質(zhì)瘤內(nèi)表達(dá)差異倍數(shù)高的mi RNA探討其在膠質(zhì)瘤內(nèi)的調(diào)節(jié)機(jī)制,并通過(guò)生物信息學(xué)軟件預(yù)測(cè)所選取mi RNA的靶基因進(jìn)行下一步研究。(2)對(duì)66例膠質(zhì)瘤組織標(biāo)本及26例正常腦組織標(biāo)本中,通過(guò)熒光定量PCR檢測(cè)mi R-218在正常腦組織及膠質(zhì)瘤內(nèi)表達(dá)量,分析miR-218在不同級(jí)別膠質(zhì)瘤內(nèi)表達(dá)情況及表達(dá)差異。(3)應(yīng)用半定量PCR初步檢測(cè)HMGB1和RAGE基因水平在不同級(jí)別膠質(zhì)瘤內(nèi)表達(dá)情況,在此基礎(chǔ)上通過(guò)定量PCR對(duì)HMGB1和RAGE基因水平在正常腦組織及膠質(zhì)瘤內(nèi)表達(dá)情況進(jìn)行驗(yàn)證,分析HMGB1和RAGE在正常腦組織及不同級(jí)別膠質(zhì)瘤內(nèi)表達(dá)情況及表達(dá)差異。(4)利用免疫組織化學(xué)方法對(duì)HMGB1和RAGE在蛋白水平表達(dá)量進(jìn)行檢測(cè),分析其在正常腦組織及膠質(zhì)瘤中陽(yáng)性細(xì)胞表達(dá)情況及表達(dá)差異,通過(guò)蛋白印跡實(shí)驗(yàn)檢測(cè)HMGB1和RAGE的在正常腦組織及膠質(zhì)瘤中表達(dá)量。(5)收集納入研究患者臨床資料并進(jìn)行隨訪。通過(guò)Kaplan-Meier方法和Cox回歸分析患者的生存曲線,進(jìn)行單變量及多變量Cox回歸分析以檢查每個(gè)臨床協(xié)變量及mi R-218、HMGB1、RAGE在膠質(zhì)瘤內(nèi)表達(dá)強(qiáng)度對(duì)患者存活的影響。結(jié)果:(1)通過(guò)對(duì)22例膠質(zhì)瘤組織標(biāo)本進(jìn)行PCR Array分析,篩選出明顯具有表達(dá)差異(Fold Difference2)的miRNA 11個(gè),(miR-22-3p、miR-363-3p、mi R-451a、mi R-20b、miR-450、mi R-149-5p、mi R-15b、miR-106b、miR-148a、mi R-93、miR-218-5p)。通過(guò)對(duì)NCBI GEO數(shù)據(jù)分析,獲取在膠質(zhì)瘤明顯具有表達(dá)差異(Fold Difference4)的miRNA 7個(gè),(miR-7、miR-10b、miR-20b、mi R-551b、miR-455、mi R-218-5p、miR-137)。依據(jù)其表達(dá)差異選取miR-218為研究對(duì)像并利用生物信息學(xué)預(yù)測(cè)mi R-218靶基因HMGB1、RAGE。(2)miR-218在正常腦組織及膠質(zhì)瘤內(nèi)均有表達(dá),在不同級(jí)別膠質(zhì)瘤內(nèi)mi R-218的表達(dá)量各不相同。與正常腦組織內(nèi)miR-218表達(dá)量相比較,miR-218表達(dá)量與腫瘤等級(jí)呈現(xiàn)逆相關(guān)。miR-218在高級(jí)別(Ⅲ級(jí)和Ⅳ級(jí))膠質(zhì)瘤組織中的表達(dá)量明顯低于低級(jí)別(Ⅰ級(jí)和Ⅱ級(jí))(p0.01)。(3)PCR、免疫組織化學(xué)染色、蛋白印跡實(shí)驗(yàn)檢測(cè)表明在正常腦組織標(biāo)本中和不同級(jí)別膠質(zhì)瘤組織標(biāo)本內(nèi)均能檢測(cè)到HMGB1、RAGE表達(dá),HMGB1、RAGE表達(dá)量與腫瘤級(jí)別正相關(guān),HMGB1、RAGE在高級(jí)別(Ⅲ級(jí)和Ⅳ級(jí))膠質(zhì)瘤組織中的表達(dá)量明顯高于低級(jí)別(Ⅰ級(jí)和Ⅱ級(jí))(p0.05)。(4)Kaplan-Meier曲線顯示低mi R-218表達(dá)患者的生存時(shí)間顯著短于mi R-218高表達(dá)的患者,Kaplan-Meier曲線顯示HMGB1、RAGE低表達(dá)組生存時(shí)間長(zhǎng)于高表達(dá)組。(5)單因素分析顯示miR-218低表達(dá)與性別(p=0.013),腫瘤大小(p=0.020),WHO分級(jí)(p0.001)和KPS評(píng)分(p0.001)顯著相關(guān),但與患者年齡以及切除程度無(wú)關(guān)。(6)Cox回歸單變量分析顯示腫瘤大小(p=0.018),WHO分級(jí)(p0.001),mi R-218表達(dá)水平(p0.001)為總生存時(shí)間(OS)的獨(dú)立相關(guān)因素;腫瘤大小(p=0.045),切除范圍(p=0.028),WHO分級(jí)(p0.001),miR-218的表達(dá)(p0.001)為無(wú)進(jìn)展生存時(shí)間(PFS)的獨(dú)立預(yù)后因子。Cox回歸多變量分析顯示mi R-218的表達(dá)(HR=0.32;95%CI 0.11,0.89;p=0.029),切除范圍(HR=0.11;95%CI 0.03,0.37;p0.001),腫瘤大小(HR=0.39;95%CI 0.14,1.11;p=0.029),和WHO分級(jí)(HR=8.94;95%CI 0.11,1.94;p0.001)是總生存時(shí)間(OS)的獨(dú)立預(yù)后因子;miR-218的表達(dá)(HR=0.46;95%CI 0.18,1.21;p=0.011),切除范圍(HR=0.09;95%CI 0.02,0.30;p0.001),腫瘤大小(HR=0.53;95%CI 0.19,1.45;p=0.031),和WHO分級(jí)(HR=2.10;95%CI 1.52,2.91;p0.001)是無(wú)進(jìn)展生存時(shí)間(PFS)的獨(dú)立相關(guān)因素。結(jié)論:PCR Array及生物信息學(xué)篩選出miRNA-218在膠質(zhì)瘤差異表達(dá),在膠質(zhì)瘤內(nèi)表達(dá)呈下調(diào)趨勢(shì)。生物信息學(xué)預(yù)測(cè)膠質(zhì)瘤內(nèi)HMGB1、RAGE為mi R-218潛在的靶基因。實(shí)驗(yàn)檢測(cè)mi R-218、HMGB1及RAGE結(jié)果表明:miR-218可作為膠質(zhì)瘤中的腫瘤抑制miRNA;miR-218在膠質(zhì)瘤中下調(diào)表達(dá)并與HMGB1和RAGE表達(dá)呈負(fù)相關(guān);mi R-218低表達(dá)與HMGB1、RAGE高表達(dá)預(yù)測(cè)膠質(zhì)瘤患者的預(yù)后不良;miR-218能通過(guò)調(diào)節(jié)HMGB1-RAGE的表達(dá)抑制膠質(zhì)瘤的進(jìn)展。
[Abstract]:Background: glioma is the most common malignant tumor in the brain, characterized by rapid invasive growth and high postoperative recurrence. The 5 year survival rate of patients with low grade glioma (WHO WHO I and II) is about 30% to 70%, and the median survival period of high grade glioblastoma (IV grade) is 9 to 12 months. Therefore, it is necessary to determine this More biomarkers and potential therapeutic targets for malignant diseases. Small RNA (microRNA, miRNA) involves a series of important biological processes, such as cell development, differentiation, apoptosis and proliferation. Abnormal mi RNA expression is related to the occurrence and progression of various tumors. In addition, the expression of the misaligned mi RNA can be used as a biomarker for the diagnosis and evaluation of the prognosis. Objective: To study the differential expression of miRNA in different grade gliomas and to explore the molecular mechanism of miRNA regulation of glial development through target gene. Methods: (1) the differential expression of MI RNA was obtained by bioinformatics on the analysis of glioma data in NCBI GEO database, and 22 cases of glioma tissue were expressed through PCR Array (containing 184miRNA primers). The pre designed PCR chip was used to screen the differential expression of MI RNA in glioma, and to select the regulatory mechanism of MI RNA in glioma, and to predict the target gene of MI RNA by bioinformatics software. (2) 66 cases of glioma tissue specimens and 26 normal brain tissues were labeled. In this study, the expression of MI R-218 in normal brain tissue and glioma was detected by fluorescence quantitative PCR, and the expression and expression difference of miR-218 in different gliomas were analyzed. (3) a semi quantitative PCR was used to detect the level of HMGB1 and RAGE in different levels of glioma, and on this basis, the quantitative PCR to HMGB1 and RAGE based on the quantitative PCR The expression and expression of HMGB1 and RAGE in normal brain tissue and different grade gliomas were verified by the expression of the level in normal brain tissue and glioma. (4) the expression of HMGB1 and RAGE in the protein level was detected by immunohistochemical method, and the positive cells in normal brain tissue and glioma were analyzed. Expression and expression difference, the expression of HMGB1 and RAGE in normal brain tissue and glioma was detected by Western blot. (5) the clinical data of the patients were collected and followed up. The survival curves of the patients were analyzed by Kaplan-Meier and Cox regression, and the single variable and multivariable Cox regression analysis were used to examine each clinical trial. The effect of covariate and MI R-218, HMGB1, RAGE on the survival of patients with glioma. Results: (1) 11 miRNA (miR-22-3p, miR-363-3p, MI) were screened by PCR Array analysis of 22 glioma tissue specimens. 148A, MI R-93, miR-218-5p). Through the analysis of NCBI GEO data, we obtain miRNA 7 miRNA (miR-7, miR-10b, miR-20b, Fold Difference4) in glioma. 2) miR-218 was expressed in normal brain tissue and glioma, and the expression of MI R-218 in different gliomas was different. Compared with miR-218 expression in normal brain tissue, the expression of miR-218 expression and tumor grade presented inverse.MiR-218 in high grade (grade III and IV grade) glioma tissue, which was significantly lower than that of low grade (grade III and IV) glioma (grade III and IV). Grade I and II) (P0.01). (3) PCR, immunohistochemical staining and Western blot test showed that HMGB1, RAGE expression, HMGB1, RAGE expression were positively correlated with tumor grade in normal brain tissue specimens and different grade glioma tissue specimens. The expression of HMGB1, RAGE in high grade (grade III and IV grade) glioma tissues was expressed. Significantly higher than the low level (grade I and grade II) (P0.05). (4) the Kaplan-Meier curve showed that the survival time of the patients with low MI R-218 expression was significantly shorter than the high expression of MI R-218, the Kaplan-Meier curve showed HMGB1, and the survival time of the RAGE low expression group was longer than that of the high expression group. (5) the single factor analysis showed that the low expression of miR-218 and sex (p=0.013), the size of the tumor ( P=0.020), WHO grading (p0.001) and KPS score (p0.001) were significantly related, but not related to patient's age and degree of resection. (6) a single variable analysis of Cox regression showed the tumor size (p=0.018), WHO classification (p0.001), MI R-218 expression level (p0.001) as an independent correlation factor for the total survival time; tumor size, resection range, etc. P0.001, miR-218 expression (p0.001) is an independent prognostic factor of progression free survival time (PFS),.Cox regression multivariable analysis shows the expression of MI R-218 (HR=0.32; 95%CI 0.11,0.89; p=0.029). 001) is an independent prognostic factor of the total survival time (OS); the expression of miR-218 (HR=0.46; 95%CI 0.18,1.21; p=0.011), the range of the resection (HR=0.09; 95%CI 0.02,0.30; p0.001), the size of the tumor (HR=0.53; 95%CI), is an independent correlation factor of the progression free survival time. Y and bioinformatics screened the differential expression of miRNA-218 in glioma. The expression in glioma was down downward. Bioinformatics predicted HMGB1 in glioma and RAGE as a potential target gene for MI R-218. Experimental detection of MI R-218, HMGB1 and RAGE results showed that miR-218 could be used as a tumor suppressor in glioma; There is a negative correlation with the expression of HMGB1 and RAGE, and the low expression of MI R-218 and the high expression of HMGB1 and RAGE predict the poor prognosis of the patients with glioma, and miR-218 can inhibit the progression of glioma by regulating the expression of HMGB1-RAGE.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R739.41

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