發(fā)布時間：2018-01-30 20:32

  本文關鍵詞： 膠質瘤 MicroRNA 轉移性 侵襲性 MMP-16　出處：《蘇州大學》2016年博士論文　論文類型：學位論文

【摘要】：背景和目的神經膠質瘤是最常見的原發(fā)性惡性腦腫瘤,具有惡性增值、血管生成和侵襲周圍正常腦組織的特征。盡管經過積極的手術、放療和化療治療,膠母細胞瘤患者的中位存活期僅僅有12-15個月。腫瘤侵襲是腫瘤治療失敗的主要原因。為延長患者生存期,提高患者生存質量,迫切需要新的臨床生物標記和治療靶點,從而提出抑制或減少腫瘤細胞侵襲能力的新治療方案。MicroRNAs(miRNAs)是一類參與調控不同生物過程的異常非編碼RNA(長度大約為22個核苷酸)。通過使用實時定量PCR發(fā)現microRNA-132(mi R-132)在膠質瘤組織中顯著異常表達�；趍iR-132靶基因的假設,我們預測miR-132和基質金屬蛋白酶(MMP)家族中的一種蛋白MMP-16(MT-MP3)有著顯著關聯。在人源膠質瘤細胞株A172,SHG44和U87中過表達miR-132可以抑制細胞侵襲和轉移。而且在A172,SHG44和U87細胞中通過使miR-132的過表達從而減少了MMP-16的表達�？偨Y以上結果分析:miR-132通過MMP-16影響膠質瘤細胞侵襲和轉移,并且在膠質瘤中miR-132作為一類抑制轉移相關基因的miRNA而存在。MicroRNAs(mi RNAs)是較短的單鏈核苷酸RNA分子,通過結合它們靶基因的mRNA分子的3'非編碼區(qū)來調控基因表達,從而抑制基因轉錄或誘導mRNA降解。miRNAs控制細胞生長、增殖、新陳代謝和凋亡。事實上,特殊類型的miRNA失調已經被證明與特定類型的腫瘤相關聯。例如,miR-16在膠質瘤細胞低表達并且抑制Bcl-2表達;在轉移性膠質瘤細胞中miR-145過表達,并且抑制ADAM17表達�；|金屬蛋白酶16(Matrix metalloprotease 16)是一類膜型金屬蛋白酶。作為酶原,通過激活proMMP-2(明膠酶A)活性來起作用。MMP-16是由細胞分泌產生。然而,酶譜顯示明膠酶激活活化的MMP-2是激活MMP-16的間接機制。MMP-2可以裂開基底膜上的膠原蛋白IV,參與腫瘤轉移過程。毫無疑問,在胃癌、肝細胞癌、前列腺癌和黑色素細胞瘤中mmp-16的高表達與腫瘤細胞侵襲力增加相關聯。本研究不僅要探討mir-132在非瘤腦組織、不同級別的人腦膠質瘤組織以及三個惡性膠質瘤細胞系(a172,shg44和u87)中的表達,而且進一步通過體外試驗探討mir-132與人腦膠質瘤細胞侵襲性的相關性。本研究還旨在為未來進一步深入研究mir-132在人類神經膠質瘤中的作用機制奠定基礎。一、材料和方法1.通過使用microrna.orgdatabase、thedatabaseonpredicted和publishedmicrornas(mirwalk),我們預測mirna-132(mir-132)與惡性腦腫瘤具有較強關聯性。2.化學合成的mir-132寡核苷酸隨機序列通過脂質體2000被轉染進惡性膠質瘤細胞株a172,shg44和u87中。3.人源膠質瘤細胞株a172,shg44和u87的轉染效率通過流式細胞術和綠色熒光檢測。4.使用實時定量pcr(qrt-pcr)分別檢測非瘤腦組織和人類膠質瘤組織標本中mir-132表達情況。5.使用transwell實驗檢測mir-132對人源膠質瘤細胞株a172,shg44和u87中的侵襲能力的影響。6.使用westernblot檢測mmp-2和mmp-16表達情況。7.熒光素酶報告實驗證明mmp-16是mir-132直接靶向基因。8.顯示的數據為均值±標準差。使用spss版本12.0windows版本軟件。使用方差分析(anova)和student'st-test進行統(tǒng)計分析。經過統(tǒng)計分析p值0.05。二、結果1.mir-132在膠質瘤組織中的表達低于正常腦組織。本研究中使用實時定量pcr檢測mir-132在11例低級別膠質瘤組織、12例高級別膠質瘤組織和8例正常腦組織中的表達情況。其實驗結果顯示:相對于正常腦組織,mir-132在膠質瘤組織中的表達顯著降低;同時與正常腦組織相比,mir-132在膠質瘤細胞株(a172,shg44和u87)中的表達更低。mir-132在膠質瘤組織和膠質瘤細胞株的下調表明mir-132也許是膠質瘤治療的潛在靶點。2.mir-132抑制膠質瘤細胞的侵襲能力。使用transwell實驗檢測mir-132對人源膠質瘤細胞株a172,shg44和u87中的侵襲能力的影響。本研究將mir-132模擬物和抑制劑被轉染進人源膠質瘤細胞a172、shg44和u87。mir-132模擬物或干擾rna轉染后的72小時,a172、shg44和u87被接種于上室,48小時后通過細胞外基質侵入的細胞被拍片和計數。在所有的細胞株中,相對于對照組,mir-132減少了侵入細胞的數量。實驗數據表明mir-132是體外實驗中細胞侵襲和遷移的調控分子。3.mmp-16mrna在膠質瘤組織的表達。實時熒光定量pcr分析表明:相對于8例正常腦組織,mmp-16mrna在11例低級別和12例高級別膠質瘤組織的表達顯著增高。結果發(fā)現:mir-132在膠質瘤組織中的表達低于正常腦組織。由此說明在腫瘤組織中mmp-16mrna的表達量較mir-132表達高,表明在腫瘤組織中mmp-16mrna的表達與mir-132的表達呈負相關。4.mir-132下調mmp-16mrna的表達。為了進一步闡明mir-132在膠質瘤細胞中抑制細胞侵襲能力的機制,本研究使用targetscan5andmirbase預測mir-132的靶基因,這些軟件顯示:mmp-16可能作為mir-132直接靶向調節(jié)基因,在腫瘤的細胞轉移和侵襲中扮演重要角色。同時運用rt-pcr實驗和qrt-pcr實驗檢測發(fā)現:與對照組細胞相比,轉染了mir-132模擬物的膠質瘤細胞(a172,shg44和u87)顯著降低了mmp-16mrna的表達水平。以上的結果表明:mmp-16可能作為mir-132直接靶向調節(jié)基因,從而抑制膠質瘤細胞的遷移和侵襲能力。5.mir-132直接靶向調節(jié)mmp-16基因的表達。本研究運用westernblot分別檢測在轉染mir-132后a172,shg44和u87中mmp-16蛋白的表達水平,其結果表明:mmp-16的蛋白表達水平在被轉染mir-132模擬物和抑制物后分別被下調和上調。進一步通過熒光素酶實驗檢測發(fā)現:mir-132直接抑制了mmp-16基因mrna的3’-utr表達,從而證實mmp-16是mir-132天然靶向調節(jié)基因。6.mmp-16作為mmp-2的活化劑激活mmp-2蛋白表達水平。mmp-16是一種膜結合型mmp,能激活mmp-2來增加侵襲能力。mmp-2被mmp-16激活,這是mmp-16功能的間接途徑。mir-132被預測靶向作用mmp-16(mt3-mmp,membranetype3mmp)(www.microrna.org)。westernblot和熒光素酶實驗被用來驗證這一假設。結果表明:miR-132通過調節(jié)MMP-16的表達從而影響MMP-2蛋白的表達;miR-132的過度表達通過下調MMP-16的表達,從而抑制人類膠質瘤細胞(A172,SHG44和U87)的侵襲能力。三、結論Has-mi R-132基因是位于17號染色體(1953202-1953302),長為100bp的堿基對。在過去的幾年里,許多研究發(fā)現miR-132異常表達參與了不同腫瘤的發(fā)生、發(fā)展過程。例如:miR-132作為腫瘤抑制器在乳腺癌中抑制細胞增殖。而且,miR-132異常表達在原發(fā)性骨肉瘤,阿爾茲海默病、前列腺癌和胰腺癌中被發(fā)現。然而,mi R-132在膠質瘤細胞遷移和侵襲中的作用仍有待探索。本研究發(fā)現miR-132的表達水平在膠質瘤組織中低于正常腦組織,而且mi R-132抑制膠質瘤細胞侵襲和遷移能力。被miR-132模擬物轉染的膠質瘤細胞(A172,SHG44和U87)減少腫瘤細胞的遷移和侵襲能力,同時用miR-132抑制劑轉染上述細胞則產生相反的結果。MMP-16是一種膜結合型MMP,能激活MMP-2來增加侵襲能力。MMP-2被MMP-16激活,這是MMP-16功能的間接途徑。目前的研究結果表明了MMP-16與膠質瘤細胞侵襲和遷移能力密切相關。以前的研究結果顯示減少的MMP-16的水平有效地抑制膠質瘤細胞的侵襲性。MMP-16同時被發(fā)現擁有抗細胞外基質組分的蛋白水解的活性,如III型膠原蛋白。在正常腦組織和星形膠質瘤組織中,MT3-MMP可能參與了細胞外基質更新。本研進一步證實miR-132通過減少基質金屬蛋白酶基因MMP-16的表達從而抑制膠質瘤細胞(A172,SHG44和U87)侵襲和遷移能力�？偠灾�,本研究證實:在惡性膠質瘤細胞中,miR-132可能通過直接調節(jié)MMP-16蛋白的表達來影響膠質瘤細胞的遷移和侵襲性中起重要作用;miR-132也許是膠質瘤侵襲和轉移的潛在治療靶點。然而,在體內試驗中,MMP-16的活性是否通過miR-132被影響需要更進一步的深入研究來確認。
[Abstract]:Background and objective: glioma is the most common primary malignant brain tumors, with malignant proliferation, angiogenesis and invasion of surrounding normal brain tissue. Despite aggressive surgery, radiotherapy and chemotherapy in the treatment of patients with glioblastoma, the median survival is only 12-15 months. Tumor invasion is the main reason the failure of cancer treatment. To prolong the survival time of the patients, improve the quality of life of patients, urgent need for clinical biomarkers and new therapeutic targets, so as to put forward a new treatment scheme to suppress or reduce the invasiveness of.MicroRNAs (miRNAs) is a kind of different biological processes involved in the regulation of the abnormal RNA (encoding length is about 22 nucleotide). By using real-time quantitative PCR microRNA-132 (MI R-132) in glioma tissues significantly. Abnormal expression of miR-132 target genes based on the hypothesis, we predicted that miR-132 and matrix metalloproteinase The enzyme (MMP) a family of protein MMP-16 (MT-MP3) has a significant correlation. In human glioma cell lines A172, SHG44 and U87 over expression of miR-132 can inhibit the invasion and metastasis of cells. But in A172, SHG44 and U87 cells by overexpression of MMP-16 reduced the expression of miR-132. Summing up the above analysis results: miR-132 through the invasion and metastasis of MMP-16 glioma cells, and miR-132 as a kind of anti metastasis related gene miRNA in glioma and the presence of.MicroRNAs (MI RNAs) is a single nucleotide RNA molecular short, mRNA molecules through the combination of their target gene 3'encoding region of controlling gene the expression of proliferation, inhibit gene transcription or mRNA induced degradation of.MiRNAs in cell growth, apoptosis, and The new supersedes the old.. In fact, a special type of miRNA disorders has been proved with a specific type of tumor associated. For example, miR-16 Low expression in glioma cells and inhibit the expression of Bcl-2 in miR-145; metastasis of glioma cells by overexpression, and inhibit the expression of ADAM17. Matrix metalloproteinase 16 (Matrix metalloprotease 16) is a kind of membrane type metalloproteinase. As a zymogen, through the activation of proMMP-2 (gelatin A enzyme) activity is produced by.MMP-16 cell secretion. However, enzyme activation of gelatinase spectrum shows that the MMP-2 is.MMP-2 indirect mechanism activation of MMP-16 can cleave the basement membrane collagen IV in the metastatic process. There is no doubt that in gastric cancer, hepatocellular carcinoma, and the high expression of mmp-16 in tumor cells of prostate cancer and melanoma invasion is associated with increased the present study not only to explore mir-132 in non tumor brain tissues and glioma tissue of different levels and three malignant glioma cell lines (A172, SHG44 and U87) in the form of, and further By in vitro test on the invasion of the relationship between mir-132 and human glioma cells. This study also aims to lay the foundation for the future further research on the mechanism of mir-132 in human gliomas. Materials and methods, 1. by using microrna.orgdatabase, thedatabaseonpredicted and publishedmicrornas (mirwalk), mirna-132 (mir-132) and we predict malignant brain tumors has the strong association of.2. chemical synthesis of mir-132 by Lipofectamine 2000 random oligonucleotide sequences were transfected into glioma cell line A172,.3. human glioma cell line A172 source SHG44 and U87, SHG44 and U87 transfection efficiency by flow cytometry and green fluorescence detection of.4. using real-time quantitative PCR (qRT-PCR) were detected respectively. Non tumor brain tissue and mir-132 in human glioma tissues the expression of.5. using Transwell assay on human mir-132 glue Glioma cell lines A172, SHG44 and U87 in the invasion effect of.6. using Westernblot to detect MMP-2 and mmp-16 expression of.7. luciferase reporter experiments prove that mmp-16 is the direct target gene.8. to display mir-132 data as mean standard deviation. Use the SPSS version of the 12.0windows version of the software. Using analysis of variance (ANOVA) and student'st-test statistics through statistical analysis analysis. The p value of 0.05. two, the expression of 1.mir-132 in glioma tissues than in normal brain tissues. Mir-132 was detected in 11 cases of low grade glioma tissues using real-time quantitative PCR in this study, the expression of 12 cases of high grade glioma tissues and 8 cases of normal brain tissues. The experimental results show that compared to the normal brain tissue, the expression of mir-132 in glioma tissues was significantly decreased; compared with normal brain tissue, mir-132 in glioma cell lines (A172, SHG44 and U87) in the table .mir-132 was lower in down regulated glioma tissues and glioma cell lines revealed that mir-132 may be a potential target for the treatment of glioma.2.mir-132 inhibits glioma cells invasion. On human glioma cell line A172 using Transwell assay, mir-132, SHG44 and U87 in the effect of invasion. This study analogue of mir-132 and inhibitor were transfected into human glioma cell line A172, SHG44 and u87.mir-132 mimic or interfere with RNA 72 hours after transfection, A172, SHG44 and U87 were seeded in the upper chamber, 48 hours after the invasion through the extracellular matrix cells were filming and counting. In all of the cell lines, compared with the control group, mir-132 reduce the number of invasive cells. The experimental data show that mir-132 is the expression and regulation of molecular.3.mmp-16mrna invasion and migration of cells in vitro in glioma tissue. Real time fluorescence quantitative PCR analysis showed that: In 8 cases of normal brain tissue, the expression of mmp-16mrna in 11 cases of low grade and 12 cases of high grade glioma tissues increased significantly. The results showed that the expression of mir-132 in glioma tissues was lower than that in normal tissues. The expression of mmp-16mrna in tumor tissues with high expression of mir-132, expression of mir-132 and mmp-16mrna showed that the expression of in tumor tissues was negatively correlated with the down-regulation of.4.mir-132 mmp-16mrna. In order to further elucidate the mechanism of mir-132 inhibition of cell invasion in glioma cells, this study used targetscan5andmirbase target gene prediction of mir-132, the software shows that the mmp-16 could be used to directly target the mir-132 regulatory gene, plays an important role in the invasion and metastasis of tumor cells at the same time. By using the RT-PCR test and qRT-PCR test showed that: compared with the control group transfected glioma cells, mir-132 mimics fine The cell (A172, SHG44 and U87) significantly reduced the expression level of mmp-16mrna. The above results showed that mmp-16 could be used to directly target the mir-132 regulating gene expression and inhibition of migration and invasion of.5.mir-132 glioma cells to target the direct regulation of mmp-16 gene. In this study the use of Westernblot A172 were detected in mir-132 after transfection, expression the level of mmp-16 protein and SHG44 in U87, the results showed that the expression of mmp-16 in transfected mir-132 mimics and inhibitor respectively is downregulated and upregulated. Further by luciferase reporter assay found that mir-132 directly inhibits mmp-16 gene mRNA 3 -utr expression, thus confirming that mmp-16 is mir-132 natural targeting gene regulation.6.mmp-16 as an activator of MMP-2 activated MMP-2 Protein expression level of.Mmp-16 is a membrane-bound MMP, can activate MMP-2 to increase the invasion ability of.Mmp-2 was mmp-16 This is the.Mir-132 activation, mmp-16 function is predicted indirectly targeting mmp-16 (mt3-mmp, membranetype3mmp) (www.microrna.org).Westernblot and luciferase assays were used to test this hypothesis. The results show that miR-132 can affect the expression of MMP-2 protein by regulating the expression of MMP-16; overexpression of miR-132 by down regulating the expression of MMP-16, thus inhibiting human glioma cells (A172, SHG44 and U87) invasion. Three. Conclusion Has-mi R-132 gene is located on chromosome 17 (1953202-1953302), 100bp long base pairs. In the past few years, many studies have found that the abnormal expression of miR-132 in different tumors, such as tumor development process. Suppressor miR-132 cell proliferation inhibition in breast cancer. Moreover, the abnormal expression of miR-132 in primary osteosarcoma, Alzheimer's disease, prostate cancer and pancreatic cancer were found in natural. However, the role of MI R-132 in the invasion and migration of glioma cells remains to be explored. This study found that the expression level of miR-132 is lower than that of normal brain tissue in glioma tissues, and MI R-132 inhibited the invasion and migration of glioma cells. MiR-132 mimics transfected glioma cells (A172, SHG44 and U87) to reduce the migration and invasion of tumor cells, and the cells were transfected with miR-132 inhibitor nterproductive.MMP-16 is a membrane-bound MMP, can activate MMP-2 to increase the invasion ability of.MMP-2 activated by MMP-16, which is indirectly the function of MMP-16. The results indicated that the MMP-16 and the invasion and migration of glioma cells closely related. Previous studies showed decreased levels of MMP-16 inhibit glioma cell invasion of.MMP-16 was also found to have anti extracellular matrix components of protein water Solution of the activity, such as type III collagen. In normal brain tissues and glioma tissues, MT3-MMP may be involved in extracellular matrix update. This study further confirmed that miR-132 can inhibit glioma cells by decreasing the expression of matrix metalloproteinase gene MMP-16 (A172, SHG44 and U87) invasion and migration. In a word, this study confirmed: in malignant glioma cells, miR-132 may directly regulate the expression of MMP-16 protein by the effect plays an important role in migration and invasion of glioma cells; miR-132 may be a potential therapeutic target in the invasion and metastasis of glioma. However, in vivo experiment, the activity of MMP-16 through miR-132 is affected further further studies to confirm.

【學位授予單位】：蘇州大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R739.41

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