MiR-127-3p在神经胶质母细胞瘤中的作用及分子机制的研究

发布时间：2018-04-13 10:50

本文选题：MiR-127-3p + 神经胶质母细胞瘤　；参考：《浙江大学》2014年博士论文

【摘要】：MicroRNA (miRNA)是长度为20-25个核苷酸的小非编码RNA,它们可以通过与靶基因3’UTR区的序列特异性结合转录后调控基因的表达。MiRNA参与多种病理生理过程,是调节细胞信号通路包括肿瘤细胞增殖和迁移的重要因子。神经胶质瘤是最常见的颅内肿瘤之一,虽然诊断和治疗技术飞速发展,恶性神经胶质瘤的预后仍然很差,其中神经胶质母细胞瘤的平均生存期只有12-15个月。神经胶质母细胞瘤的发生和发展是一个多步骤的过程,期间受到很多因子的调控。最近几年很多学者对miRNA在神经胶质母细胞瘤发生发展中的作用进行了深入的研究。本文的第一部分,我们通过第二代高通量测序以及荧光定量PCR发现与正常脑组织相比miR-127-3p在神经胶质母细胞瘤组织中表达量下调。进一步研究显示DNA的甲基化和组蛋白去乙酰基化造成了miR-127-3p表达量的下调。我们通过体内外实验证实了miR-127-3p通过诱导G1期阻滞抑制了神经胶质母细胞瘤细胞的生长。另外我们证实了miR-127-3p的五个靶基因SKI,RGMA,ZWINT,SERPINB9和SFRP1,最后我们发现miR-127-3p通过抑制原癌基因SKI激活起到肿瘤抑制作用的TGF-β信号通路抑制神经胶质母细胞瘤细胞的增殖。据我们所知,SKI在神经胶质瘤中的作用还未被报道过,我们的研究首次提出了SKI在神经胶质母细胞瘤中发挥作用的证据。本文第二部分,我们发现五个人类神经胶质母细胞瘤细胞系中miR-127-3p的表达量与细胞的迁移和侵袭能力正相关。经体外细胞系和裸鼠体内实验均证实miR-127-3p促进神经胶质母细胞瘤细胞的迁移和侵袭。证实了已被报道抑制神经胶质母细胞瘤迁移和侵袭的肿瘤抑制因子SEPT7是miR-127-3p的靶基因,并且SEPT7能够部分抑制miR-127-3p对细胞迁移和侵袭的促进作用。另外芯片数据显示miR-127-3p能够调控更多与细胞迁移和侵袭相关的基因。最后我们证实在神经胶质母细胞瘤细胞miR-127-3p通过调节SEPT7影响F-actin细胞骨架的重塑。我们的研究表明,miR-127-3p在神经胶质母细胞瘤中是一个关键因子,也是一个潜在的神经胶质母细胞瘤治疗靶点。
[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.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R739.4

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