食管鳞癌中差异表达microRNAs的致癌机制研究

发布时间：2018-03-25 12:52

本文选题：食管鳞癌　切入点：miRNAs　出处：《昆明理工大学》2017年硕士论文

【摘要】：食管癌(EsophagealCarcinoma,EC)是最常见的消化道恶性肿瘤之一,其死亡率列恶性肿瘤第四位,5年生存率不到15%。在中国,食管鳞状细胞癌(Esophageal Squamous Cell Carcinoma,ESCC)是最主要的病理类型,具有易复发和易转移等特点。目前,手术切除和放化疗是食管癌治疗的主要方式,但由于食管癌在发病早期缺乏典型的临床症状和有效的诊断技术,食管癌发现时多数已经处在中晚期,治疗效果并不理想。因此,研究早期诊断食管癌的方法,并从分子水平探究食管癌的发生发展机制,对食管癌的早期诊断和治疗具备重要意义。微小RNAs(miRNAs)是一类内源性的,长度约为20-24个核苷酸的非编码RNA,通过与靶基因的3' UTR区结合抑制基因转录后的翻译和蛋白编码基因的表达。miRNAs是在癌细胞的增殖、分化、衰老、凋亡和转移等生物过程中发挥着重要作用。miRNAs在不同的恶性肿瘤中其生物学功能不同,最主要的原因是其调控的靶基因不同。不同的miRNAs可能调控着同一个靶基因,而一个miRNA可以调节许多不同的靶基因。miRNAs靶基因的预测是研究miRNAs作用机制的关键环节。因此,揭示肿瘤中差异表达的miRNAs与靶基因之间调控的关系是至关重要的。在论文中,我们深入研究了三个抑癌作用的miRNAs(miR-99a、miR-145和miR-125b)和一个具有致癌作用的miRNA(miR-1470)在食管癌变中的作用及其分子机制。首先通过miRNA表达谱芯片技术发现在食管鳞癌组织中miR-99a、miR-145和miR-125b表达显著下调;miR-1470在食管鳞癌组织中表达显著上调。通过分析GEO-Dateset数据库,我们发现在GSE43732、GSE59973和GSE61047数据集中miR-99a、miR-145和miR-125b在食管鳞癌组织中表达同样显著下调,这些数据进一步验证了我们的芯片结果。接下来我们在体外细胞模型中研究了miR-99a、miR-145和miR-125b在食管癌变过程中的作用,结果发现过表达miR-99a、miR-145和miR-125b可以显著抑制食管鳞癌细胞的增殖、迁移和侵袭过程分子水平的研究进一步发现miR-99a、miR-145和miR-125b通过调节细胞周期蛋白CCNA2、CCND1和CCNE1的mRNA水平从而抑制食管鳞癌细胞的增殖。miR-99a、miR-145和miR-125b通过调节Slug诱导的EMT和MMPs分子从而抑制食管鳞癌细胞的迁移和侵袭过程。miRNAs通过调节靶基因的3' UTR在肿瘤中发挥重要的功能。我们通过分子生物信息学数据库并结合文献报道发现miR-99a、miR-145和miR-125b通过各自的靶基因调控着肿瘤的恶性表型。我们发现miR-99a通过负调节靶基因IGF1R作用于食管鳞癌细胞增殖、迁移和侵袭过程。miR-145通过负调节靶基因SP1作用于食管鳞癌细胞增殖、衰老、迁移和侵袭过程。miR-125b通过负调节靶基因HMGA2作用于食管鳞癌细胞增殖、衰老、迁移和侵袭过程。本论文重点研究了食管鳞癌中差异表达miRNAs的致癌作用及其分子机制。通过本论文的研究将为揭示食管癌细胞增殖和侵袭运动的分子机制提供理论依据,并为食管鳞癌的诊断和治疗提供新型生物标志物和治疗靶点。
[Abstract]:Esophageal cancer (EsophagealCarcinoma, EC) is one of the most common malignant tumor of digestive tract, the mortality rate of malignant tumors among the fourth, 5 year survival rate is less than 15%. in Chinese, esophageal squamous cell carcinoma (Esophageal Squamous Cell Carcinoma, ESCC) is the main pathological type, with recurrence and metastasis characteristics at present. Surgical resection, and chemotherapy is the main treatment of esophageal cancer, but due to lack of typical clinical symptoms of esophageal carcinoma and effective diagnostic technique in the pathogenesis of early esophageal cancer, the majority found already in advanced treatment, the effect is not ideal. Therefore, the research method of early diagnosis of esophageal cancer, and to explore the mechanism of the occurrence and development of esophageal cancer at the molecular level, has important significance to the early diagnosis and treatment of esophageal carcinoma. Micro RNAs (miRNAs) is a class of endogenous, non RNA encoding length of about 20-24 nucleotides, with the target substrate Because the 3'UTR binding protein encoding gene translation and expression of.MiRNAs inhibit the post transcriptional gene is in cancer cell proliferation, differentiation, senescence, apoptosis and metastasis biology plays an important role in the process of.MiRNAs in different malignant tumor in its biological function, the main reason is the different target genes and its regulation the different miRNAs may regulate the same target gene prediction, and a miRNA can regulate many different target genes of.MiRNAs target genes is a key link to study the action mechanism of miRNAs. Therefore, the relationship between miRNAs and reveal the regulation of target gene expression in different tumors is very important. In this paper, we study three the role of tumor suppressor miRNAs (miR-99a, miR-145 and miR-125b) and has a carcinogenic effect of miRNA (miR-1470) and its role in molecular mechanism of esophageal carcinogenesis in the first through the miRNA. Microarray found miR-99a in esophageal squamous cell carcinoma, miR-145 and miR-125b expression were significantly reduced; significantly up-regulated expression of miR-1470 in esophageal squamous cell carcinoma. Through the analysis of the GEO-Dateset database, we found in GSE43732, GSE59973 and GSE61047 data from miR-99a, the expression of miR-145 and miR-125b in esophageal squamous cell carcinoma were also significantly reduced, these data further verified our microarray results. Then we studied the miR-99a in vitro cell model, the role of miR-145 and miR-125b in esophageal carcinogenesis. Results showed that over expression of miR-99a, miR-145 and miR-125b can significantly inhibit proliferation of esophageal squamous cell carcinoma cell proliferation, migration and invasion of molecular level further found that miR-99a, miR-145 and miR-125b by regulating cell cycle protein CCNA2, CCND1 and CCNE1 levels of mRNA and inhibit the cell proliferation of.M esophageal squamous cell carcinoma IR-99a, miR-145 and miR-125b by adjusting the EMT and MMPs molecules induced by Slug and inhibited.MiRNAs migration and invasion of esophageal squamous cell carcinoma cells play an important role in tumor by regulating target gene 3'UTR. We through molecular bioinformatics databases and literatures reported that miR-99a, miR-145 and miR-125b through the regulation of their target genes the malignant phenotype of tumor. We found miR-99a by negatively regulating the target gene of IGF1R in esophageal squamous cell carcinoma cell proliferation, migration and invasion of.MiR-145 through the negative regulation of target gene SP1 in esophageal squamous cell carcinoma cell proliferation, senescence, migration and invasion of.MiR-125b through the negative regulation of target gene HMGA2 in esophageal squamous cell carcinoma cell proliferation, migration and aging. The invasion process. This paper focuses on the study of the differences in expression of miRNAs esophageal squamous cell carcinogenesis and its molecular mechanism. Through this paper This study will provide a theoretical basis for revealing the molecular mechanism of esophageal cancer cell proliferation and invasion, and provide new biomarkers and therapeutic targets for the diagnosis and treatment of esophageal squamous cell carcinoma.

【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.1

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