本文選題：胃癌　切入點：復(fù)合基因調(diào)控網(wǎng)絡(luò)　出處：《華東理工大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：胃癌(GastricCancer,GC)是全世界范圍內(nèi)發(fā)病率和死亡率最高的癌癥類型之一。盡管已經(jīng)鑒定出很多與胃癌相關(guān)的基因(gene)和microRNA(miRNA),但它們在系統(tǒng)層面的作用機理仍然不清楚。為了在系統(tǒng)層面探究胃癌形成過程中的異常調(diào)控機制,本課題建立了用來識別癌癥相關(guān)調(diào)控關(guān)系的方法,該方法創(chuàng)造性地整合了差異調(diào)控、差異表達及調(diào)控子(Regulator)對靶基因調(diào)控效應(yīng)三方面的信息,并將該方法用于胃癌組學(xué)數(shù)據(jù)研究胃癌發(fā)生發(fā)展的機制。本課題基于TCGA胃癌mRNA和miRNA表達數(shù)據(jù),首先用差異共表達分析(Differential Coexpression Analysis,DCEA)策略獲得一組在正常和癌癥狀態(tài)之間表達水平的相關(guān)性發(fā)生顯著變化的gene和miRNA(gene/miRNA),并用這些gene/miRNA分別構(gòu)建正常和癌癥條件下包含轉(zhuǎn)錄因子(Transcriptional Factor,TF)和miRNA的條件特異的復(fù)合基因調(diào)控網(wǎng)絡(luò)(combinational Gene Regulatory Network,cGRN),發(fā)現(xiàn)條件特異的cGRN能顯著富集已知的癌癥相關(guān)的gene/miRNA;然后建立了度量不同條件下調(diào)控關(guān)系差異的方法,發(fā)現(xiàn)該方法能將癌癥相關(guān)的gene/miRNA顯著地排在前面,并用該方法篩選調(diào)控強度發(fā)生顯著變化的調(diào)控關(guān)系;隨后,通過整合差異調(diào)控、差異表達及Regulator對靶基因因的調(diào)控效應(yīng)三方面的信息定義了差異調(diào)控關(guān)系(Differentially Regulated Link,DRL);最后,通過整合DRL及臨床生存時間數(shù)據(jù),篩選出三個關(guān)鍵的Regulator,TCF7L1、TCF4和MEIS1。圍繞這三個Regulator,及其相關(guān)的DRL,結(jié)合文獻信息,在系統(tǒng)水平上提出了一個胃癌發(fā)生的異常調(diào)控機制假說。在該項研究中,miRNA微調(diào)效應(yīng)在系統(tǒng)層面被觀察到。此外,本課題還將差異調(diào)控分析方法應(yīng)用到中國人胃癌表達譜數(shù)據(jù)GSE54129中,對癌癥和癌旁之間的差異調(diào)控基因(Differentially Regulated Genes,DRG)和差異調(diào)控關(guān)系(DRL)排序。從計算的結(jié)果中選取排在最靠前的一個TF CREB1,及兩個靶基因TCEAL2和MBNL1,用分子生物學(xué)實驗重現(xiàn)了預(yù)測的這兩個調(diào)控關(guān)系在正常和癌癥條件下的差異調(diào)控結(jié)果。本課題提出的胃癌機制假說能為今后的研究提供指導(dǎo),構(gòu)建的差異調(diào)控分析策略還可以用于探索其它復(fù)雜疾病以及表型變化現(xiàn)象背后的基因表達調(diào)控機制。
[Abstract]:Gastric cancer is one of the most common cancer types with the highest morbidity and mortality in the world. Although many genes related to gastric cancer gene genetics and microRNAs miRNAs have been identified, the mechanism of their action at the system level is still unclear. To explore the mechanism of abnormal regulation in the formation of gastric cancer, In this study, a method was developed to identify cancer-related regulatory relationships. This method creatively integrates information on differential regulation, differential expression and regulatory effects of regulators on target genes. The method was used to study the mechanism of gastric carcinogenesis and development in gastric cancer. This study was based on mRNA and miRNA expression data of TCGA gastric cancer. First, differential Coexpression Analysis (DCEA) strategy was used to obtain a group of gene and miRNAgene / miRNAs with significantly different expression levels between normal and cancer states, and these gene/miRNA were used to construct transcription factors under normal and cancer conditions, respectively. The combined Gene Regulatory Network (CGRN) and the conditional specific gene regulatory network of miRNA found that conditional cGRN significantly enriched known cancer-related gene / miRNAs, and then established a method to measure differences in regulatory relationships under different conditions. It was found that this method can significantly rank the cancer related gene/miRNA in the first place, and screen out the regulatory relationships with significant changes in regulatory intensity by using this method, and then, by integrating differential regulation, Differential expression and the regulatory effect of Regulator on target gene cause define differential Regulated link DRL. Finally, by integrating DRL and clinical survival time data, Three key Regulators, TCF7L1, TCF4 and MEIS1, were screened around the three Regulators, and their associated DRLs, combined with literature information, A hypothesis of abnormal regulatory mechanism for gastric carcinogenesis has been proposed at the systemic level. In this study, the effect of miRNA fine-tuning was observed at the systemic level. The method of differential regulation analysis was also applied to Chinese gastric cancer expression profile data GSE54129. The differential Regulated genes (DRGs) and differential regulatory relationships (DRLs) were sequenced between cancer and adjacent cancer. The TF CREB1, two target genes TCEAL2 and MBNL1 were selected from the calculated results, and predicted by molecular biological experiments. The results of these two regulatory relationships are different in normal and cancer conditions. The hypothesis of gastric cancer mechanism proposed in this paper can provide guidance for future research. The strategy can also be used to explore the gene expression regulation mechanism behind other complex diseases and phenotypic changes.
【學(xué)位授予單位】：華東理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R735.2

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