阿霉素和miR-21抑制剂联用对胶质瘤协同抑制作用机制的研究

发布时间：2018-06-18 15:53

本文选题：甲基化 + 阿霉素　；参考：《天津大学》2014年硕士论文

【摘要】：表观遗传学修饰的DNA甲基化在胶质瘤的发生发展中起重要作用。启动子区抑癌基因的高甲基化与肿瘤的关系最为密切,它是抑癌基因转录失活的主要途径。研究发现化疗药物阿霉素DOX和微小RNA均可参与肿瘤的甲基化。本文基于甲基化过程中重要的甲基转移酶DNMT1为切入点,以胶质瘤为模型,首先研究阿霉素对DNMT1表达的影响及其抑制肿瘤机制,同时从基因水平,分析miR-21对DNMT1的调控作用,探索miR-21与甲基化的关系。进一步将阿霉素与miR-21抑制剂联用,探讨了两者协同抑制胶质瘤的效果及其机制。以U87、U87-EGFRvIII和LN229三种胶质瘤细胞为模型,对上述机制进行研究。结果表明,三种细胞系经阿霉素独立处理后,DNMT1的蛋白表达水平和mRNA表达水平均有明显的下调,甲基化相关编码基因PTEN和p21的表达水平则明显上调,非编码基因miR-200a/b/429和mi R-181d也出现不同程度的上调。当miR-21抑制剂独立处理三个细胞系之后,DNMT1的蛋白表达水平下调,E-cadherin、RECK、PTEN、VHL及mi R-200a/b/429和miR-181d表达水平上调。证明了阿霉素和miR-21在DNA甲基化中具有重要作用。联合使用阿霉素与miR-21抑制剂,显著增强了三种细胞系E-cadherin、RECK、PTEN、VHL、p21及miR-200a/b/429和miR-181d的表达水平,并使三种细胞系增值率显著降低,侵袭和迁移能力下降。本研究证明,阿霉素联合miR-21抑制剂调控DNA甲基化是胶质瘤治疗的新策略,为胶质瘤的预测和治疗提供了一种新的研究方案。
[Abstract]:Epigenetic modification of DNA methylation plays an important role in the development of glioma. Hypermethylation of tumor suppressor gene in promoter region is most closely related to tumor, which is the main pathway of transcription inactivation of tumor suppressor gene. It has been found that both doxorubicin dox and microRNA are involved in tumor methylation. Based on DNMT1, an important methylation enzyme in the process of methylation, and taking glioma as a model, the effects of adriamycin on the expression of DNMT1 and the mechanism of its inhibition were studied. At the same time, the regulatory effect of miR-21 on DNMT1 was analyzed at the gene level. To explore the relationship between miR-21 and methylation. Furthermore, the synergistic effect of doxorubicin and miR-21 inhibitor on glioma and its mechanism were discussed. Three kinds of glioma cells, U87-EGFRvIII and LN229, were used as models to study the mechanism. The results showed that the protein expression and mRNA expression of DNMT1 were significantly down-regulated in the three cell lines treated independently with adriamycin, while the expression levels of methylation-associated coding genes PTEN and p21 were significantly up-regulated. Noncoding genes miR-200a / br429 and miR-181d were also up-regulated to varying degrees. When miR-21 inhibitor treated three cell lines independently, the protein expression level of DNMT1 down-regulated the expression levels of E-cadherin, RECK, PTEN, VHL, mi R-200a/ b / 429 and miR-181d. It is proved that adriamycin and miR-21 play an important role in DNA methylation. The combination of adriamycin and miR-21 inhibitor significantly enhanced the expression levels of E-cadherinon RECKTN PTEN, miR-200a/ b / 429 and miR-181d, and significantly decreased the proliferation rate, invasion and migration ability of the three cell lines. This study demonstrated that the regulation of DNA methylation by adriamycin and miR-21 inhibitor is a new strategy for glioma therapy and provides a new research scheme for the prediction and treatment of glioma.
【学位授予单位】：天津大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R739.41

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