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  本文選題：MiR-127-3p + 神經(jīng)膠質(zhì)母細(xì)胞瘤��； 參考：《浙江大學(xué)》2014年博士論文

【摘要】：MicroRNA (miRNA)是長度為20-25個核苷酸的小非編碼RNA,它們可以通過與靶基因3’UTR區(qū)的序列特異性結(jié)合轉(zhuǎn)錄后調(diào)控基因的表達(dá)。MiRNA參與多種病理生理過程,是調(diào)節(jié)細(xì)胞信號通路包括腫瘤細(xì)胞增殖和遷移的重要因子。神經(jīng)膠質(zhì)瘤是最常見的顱內(nèi)腫瘤之一,雖然診斷和治療技術(shù)飛速發(fā)展,惡性神經(jīng)膠質(zhì)瘤的預(yù)后仍然很差,其中神經(jīng)膠質(zhì)母細(xì)胞瘤的平均生存期只有12-15個月。神經(jīng)膠質(zhì)母細(xì)胞瘤的發(fā)生和發(fā)展是一個多步驟的過程,期間受到很多因子的調(diào)控。最近幾年很多學(xué)者對miRNA在神經(jīng)膠質(zhì)母細(xì)胞瘤發(fā)生發(fā)展中的作用進(jìn)行了深入的研究。 本文的第一部分,我們通過第二代高通量測序以及熒光定量PCR發(fā)現(xiàn)與正常腦組織相比miR-127-3p在神經(jīng)膠質(zhì)母細(xì)胞瘤組織中表達(dá)量下調(diào)。進(jìn)一步研究顯示DNA的甲基化和組蛋白去乙�；斐闪薽iR-127-3p表達(dá)量的下調(diào)。我們通過體內(nèi)外實驗證實了miR-127-3p通過誘導(dǎo)G1期阻滯抑制了神經(jīng)膠質(zhì)母細(xì)胞瘤細(xì)胞的生長。另外我們證實了miR-127-3p的五個靶基因SKI,RGMA,ZWINT,SERPINB9和SFRP1,最后我們發(fā)現(xiàn)miR-127-3p通過抑制原癌基因SKI激活起到腫瘤抑制作用的TGF-β信號通路抑制神經(jīng)膠質(zhì)母細(xì)胞瘤細(xì)胞的增殖。據(jù)我們所知,SKI在神經(jīng)膠質(zhì)瘤中的作用還未被報道過,我們的研究首次提出了SKI在神經(jīng)膠質(zhì)母細(xì)胞瘤中發(fā)揮作用的證據(jù)。 本文第二部分,我們發(fā)現(xiàn)五個人類神經(jīng)膠質(zhì)母細(xì)胞瘤細(xì)胞系中miR-127-3p的表達(dá)量與細(xì)胞的遷移和侵襲能力正相關(guān)。經(jīng)體外細(xì)胞系和裸鼠體內(nèi)實驗均證實miR-127-3p促進(jìn)神經(jīng)膠質(zhì)母細(xì)胞瘤細(xì)胞的遷移和侵襲。證實了已被報道抑制神經(jīng)膠質(zhì)母細(xì)胞瘤遷移和侵襲的腫瘤抑制因子SEPT7是miR-127-3p的靶基因,并且SEPT7能夠部分抑制miR-127-3p對細(xì)胞遷移和侵襲的促進(jìn)作用。另外芯片數(shù)據(jù)顯示miR-127-3p能夠調(diào)控更多與細(xì)胞遷移和侵襲相關(guān)的基因。最后我們證實在神經(jīng)膠質(zhì)母細(xì)胞瘤細(xì)胞miR-127-3p通過調(diào)節(jié)SEPT7影響F-actin細(xì)胞骨架的重塑。 我們的研究表明,miR-127-3p在神經(jīng)膠質(zhì)母細(xì)胞瘤中是一個關(guān)鍵因子,也是一個潛在的神經(jīng)膠質(zhì)母細(xì)胞瘤治療靶點。
[Abstract]:MicroRNA miRNAs are small noncoding RNAs with a length of 20-25 nucleotides. They can be involved in many pathophysiological processes by specifically binding the expression of post-transcriptional genes to the 3'UTR region of the target gene.It is an important factor in regulating cell signaling pathway, including tumor cell proliferation and migration.The occurrence and development of glioblastoma is a multi-step process, which is regulated by many factors.In recent years, many scholars have studied the role of miRNA in the development of glioblastoma.In the first part of this paper, we found that the expression of miR-127-3p was down-regulated in glioblastoma tissues compared with normal brain tissues by second generation high-throughput sequencing and fluorescence quantitative PCR.Further studies showed that methylation of DNA and deacetylation of histone resulted in down-regulation of miR-127-3p expression.We confirmed in vitro and in vivo that miR-127-3p inhibited the growth of glioblastoma cells through G 1 arrest.In addition, we confirmed the five target genes of miR-127-3p, SKIRGMA-ZWINTINPINB9 and SFRP1. Finally, we found that miR-127-3p inhibits the proliferation of glioblastoma cells by inhibiting the TGF- 尾 signaling pathway, which activates tumor inhibition by the proto-oncogene SKI.The role of SKI in glioma has not been reported, and our study provides evidence for the role of SKI in glioblastoma for the first time.In the second part, we found that the expression of miR-127-3p in five human glioblastoma cell lines was positively correlated with cell migration and invasion.Both in vitro and in vivo experiments confirmed that miR-127-3p promoted the migration and invasion of glioblastoma cells.It is confirmed that the tumor suppressor SEPT7, which has been reported to inhibit the migration and invasion of glioblastoma, is a target gene of miR-127-3p, and SEPT7 can partially inhibit the promotion of cell migration and invasion by miR-127-3p.In addition, chip data show that miR-127-3p can regulate more genes related to cell migration and invasion.Finally, we confirm that in glioblastoma cells miR-127-3p affects the remodeling of F-actin cytoskeleton by regulating SEPT7.Our results suggest that miR-127-3p is a key factor in glioblastoma and a potential therapeutic target for glioblastoma.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R739.4

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1 蔣華蔚;MiR-127-3p在神經(jīng)膠質(zhì)母細(xì)胞瘤中的作用及分子機(jī)制的研究[D];浙江大學(xué);2014年

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本文編號：1744176