本文選題：結(jié)腸直腸癌 + 基因表達(dá)�。� 參考：《武漢大學(xué)》2016年博士論文

【摘要】：背景：結(jié)腸直腸癌是一種高度異質(zhì)性疾病,具有多種分子表型和基因組變異特征,其基因的異常表達(dá)與癌細(xì)胞的發(fā)生和發(fā)展密切相關(guān)。然而,具有高度惡性的結(jié)腸直腸低分化腺癌組織的基因表達(dá)和基因組改變特征仍不十分清楚。目的：旨在深入了解Ⅱ期結(jié)腸直腸低分化腺癌組織中的基因改變及其惡性表型的相關(guān)性。方法：我們收集了四對(duì)Ⅱ期低分化結(jié)腸直腸腺癌組織和對(duì)應(yīng)癌旁正常組織,利用包含有440個(gè)腫瘤相關(guān)基因的表達(dá)譜芯片和聚類(lèi)分析獲得顯著差異表達(dá)基因；生物信息學(xué)Gene Ontology和Ingenuity,Pathway Analysis分析腫瘤組織中的差異表達(dá)基因參與的信號(hào)通路及相關(guān)的生物學(xué)功能；利用新型的生物信息學(xué)計(jì)算機(jī)模型預(yù)測(cè)了差異表達(dá)基因的轉(zhuǎn)錄調(diào)控機(jī)制；結(jié)合腫瘤基因組圖譜數(shù)據(jù)(TCGA)中的195例結(jié)腸直腸癌組織高通量測(cè)序及基因表達(dá)數(shù)據(jù),進(jìn)行比對(duì)分析獲得表達(dá)差異基因的基因組變異特征；通過(guò)文獻(xiàn)檢索獲得與臨床表型相關(guān)的50個(gè)基因芯片實(shí)驗(yàn)數(shù)據(jù)進(jìn)行比對(duì)分析,并結(jié)合常見(jiàn)實(shí)體腫瘤的基因組圖譜信息,進(jìn)一步驗(yàn)證和篩選與結(jié)腸直腸癌進(jìn)展高度相關(guān)的基因；利用免疫組織化學(xué)染色驗(yàn)證候選基因的蛋白表達(dá)情況與臨床惡性表型的相關(guān)性。結(jié)果：在Ⅱ期低分化結(jié)腸直腸腺癌組織與其對(duì)應(yīng)癌旁正常組織中,共獲得93個(gè)差異表達(dá)基因(表達(dá)差異1.5倍以上,p小于0.05)；聚類(lèi)分析結(jié)果顯示,在腫瘤組織內(nèi)包含顯著表達(dá)上調(diào)基因群和顯著表達(dá)下調(diào)基因群；系統(tǒng)生物信息學(xué)分析結(jié)果顯示差異表達(dá)基因主要參與細(xì)胞凋亡、磷酸化、細(xì)胞周期調(diào)控等生物學(xué)過(guò)程,在癌組織中以NFKB、p53、AP1、STAT1、HSP90和CTNNB1信號(hào)通路紊亂最為顯著；同時(shí),依據(jù)生物信息學(xué)原理預(yù)測(cè)與差異表達(dá)基因相關(guān)的7個(gè)轉(zhuǎn)錄因子包括NFKB1、RELA、AP1、STAT3、p53和p63及其轉(zhuǎn)錄調(diào)控關(guān)系；與TCGA數(shù)據(jù)庫(kù)比對(duì)分析,篩選出24個(gè)mRNA表達(dá)相一致的基因,其基因組變異頻率在5%-37%；其中14個(gè)基因呈現(xiàn)拷貝數(shù)增加或減少,且mRNA表達(dá)量與其拷貝數(shù)變化密切相關(guān)；結(jié)合50個(gè)基因芯片實(shí)驗(yàn)數(shù)據(jù)共篩選出8個(gè)候選基因與腫瘤惡性表型具有潛在相關(guān)性,包括RPN2,HMGB1,AARS,IGFBP3,STAT1,YOU1,NQO1 and PEA15;在9種不同類(lèi)型的實(shí)體腫瘤比較研究中,PRN2和HMGB1在結(jié)腸直腸癌中的變異頻率最高；免疫組化實(shí)驗(yàn)結(jié)果顯示在78例結(jié)腸直腸癌樣本中,RPN2和HMGB1蛋白表達(dá)在癌組織中顯著高表達(dá),RPN2與組織分化程度和轉(zhuǎn)移存在顯著相關(guān)性。結(jié)論：本研究通過(guò)差異基因表達(dá)譜結(jié)合基因組數(shù)據(jù)庫(kù)、不同的人群的基因芯片實(shí)驗(yàn)數(shù)據(jù),共篩選出八個(gè)與腫瘤轉(zhuǎn)移高度相關(guān)的候選基因,并揭示了RPN2和HMGB1在結(jié)腸直腸癌中作為早期腫瘤轉(zhuǎn)移預(yù)測(cè)的分子標(biāo)記物和RNAi藥物靶標(biāo)的潛在的臨床應(yīng)用價(jià)值。
[Abstract]:Background: colorectal cancer is a highly heterogeneous disease with a variety of molecular phenotypes and genomic variations. The abnormal expression of the gene is closely related to the occurrence and development of cancer cells. However, the gene expression and genomic changes of highly malignant colorectal adenocarcinoma tissue are still not very clear. The purpose of this study is to understand the correlation between gene change and its malignant phenotype in stage II colorectal carcinoma with low differentiation. Methods: We collected four pairs of low differentiated colorectal adenocarcinoma tissues and normal tissues adjacent to the carcinoma, and obtained significant differential expression by using expression profiles and cluster analysis containing 440 tumor related genes. Gene; bioinformatics Gene Ontology and Ingenuity, Pathway Analysis to analyze the signaling pathway and related biological functions of differentially expressed genes in tumor tissues; use a new bioinformatics computer model to predict the transcriptional regulation mechanism of differentially expressed genes; combined with the tumor genome map data (TCGA). High throughput sequencing and gene expression data of 195 cases of colorectal cancer were compared and analyzed to obtain genomic variation characteristics of differentially expressed genes. 50 gene chip experimental data related to clinical phenotype were compared and analyzed by literature retrieval, and combined with the genome map information of common solid tumors, it was further verified. And screening the genes associated with the progression of colorectal cancer, and using immunohistochemical staining to verify the correlation between the protein expression of the candidate gene and the clinical malignant phenotype. Results: 93 differentially expressed genes (1.5 times of the difference in expression) were obtained in stage II low differentiated colorectal adenocarcinoma and corresponding to the normal tissue adjacent to the carcinoma. P was less than 0.05), and the results of cluster analysis showed that the up-regulated gene group and down regulated gene group were significantly expressed in the tumor tissues. The system bioinformatics analysis showed that the differentially expressed genes were mainly involved in the biological process of cell apoptosis, phosphorylation, cell cycle regulation, and NFKB, p53, AP1, STAT1, HSP90 in the cancer tissues. At the same time, the 7 transcription factors related to differentially expressed genes were predicted by bioinformatics principles, including NFKB1, RELA, AP1, STAT3, p53 and p63, and their transcriptional regulation relationships. 24 mRNA tables were screened out with the same gene as TCGA database, and the frequency of genomic variation was in 5%-37%; 7 14 genes showed an increase or decrease in the number of copies, and the expression of mRNA was closely related to the change in the number of copies. A total of 8 candidate genes were screened with 50 gene chip data to be associated with the malignant phenotype of tumor, including RPN2, HMGB1, AARS, IGFBP3, STAT1, YOU1, NQO1 and PEA15, and 9 different types of solid tumor ratio. In the comparative study, PRN2 and HMGB1 had the highest frequency of variation in colorectal cancer; the immunohistochemical results showed that the expression of RPN2 and HMGB1 protein expressed significantly in the cancer tissues in 78 cases of colorectal cancer, and there was a significant correlation between RPN2 and the degree of tissue differentiation and metastasis. A total of eight candidate genes associated with tumor metastasis were screened from the group database and the gene chip experimental data of different populations, and the potential clinical application value of RPN2 and HMGB1 in colorectal cancer as a molecular marker and RNAi drug target for early tumor metastasis prediction was revealed.

【學(xué)位授予單位】：武漢大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R735.3

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