【摘要】：結(jié)直腸癌是最常見的惡性腫瘤之一,嚴重危害人類生命健康。根據(jù)基因表達情況,結(jié)直腸癌可分為5種亞型。其中之一為炎癥型腸癌。本研究利用生物信息學(xué)方法觀察了相關(guān)炎癥因子在人類炎癥型腸癌的表達變化,并建立了結(jié)腸炎相關(guān)結(jié)腸癌的小鼠模型,獲得了炎癌轉(zhuǎn)化小鼠模型的基因表達數(shù)據(jù),并初步驗證了相關(guān)炎癥因子在動物模型中的表達變化,與人類炎癥型腸癌進行了對比。(第一部分)結(jié)直腸癌的分子分型是近來臨床關(guān)注和研究的重點和熱點。而炎癌轉(zhuǎn)化研究也越來越多地被研究者所關(guān)注。大量研究提示并證實了炎癥轉(zhuǎn)化為腫瘤的過程的存在,但并非所有的腫瘤都由炎癥轉(zhuǎn)化而來。本研究僅關(guān)注炎癥型腸癌的若干炎癥因子基因表達變化。本部分研究使用TCGA數(shù)據(jù)庫下載的人類結(jié)直腸癌患者及癌旁組織的基因組數(shù)據(jù),使用生物信息學(xué)方法,將結(jié)直腸癌分為包括炎癥型腸癌在內(nèi)的5類,并分析了ILIA、IL1B、IL6、IL23A、NFKB2、TGFB1、 TGFB3、PTGS2幾個基因在人類炎癥型腸癌的變化情況。結(jié)果發(fā)現(xiàn)在TCGA數(shù)據(jù)庫647例腸癌中,98例腸癌被分型為炎癥型腸癌,在炎癥型腸癌中,上述8個基因均呈高表達。(第二部分)TCGA數(shù)據(jù)庫的樣本來源受地域、人種等因素影響,而針對不同遺傳背景、不同地區(qū)人群,臨床研究所取得的結(jié)果不盡相同。本部分研究使用我院臨床患者的樣本,使用生物信息學(xué)方法,將67例患者中的10例聚類至炎癥型腸癌,并分析了ILIA、IL1B、IL6、IL23A、NFKB2、TGFB1、TGFB3、PTGS2幾個基因在人類炎癥型腸癌的變化情況,結(jié)果發(fā)現(xiàn),上述幾個基因均呈高表達,且變化趨勢與TCGA數(shù)據(jù)庫的結(jié)果一致。(第三部分)動物模型在疾病的病理機制的研究中一直有著無可替代的作用。在炎癥相關(guān)性腸癌的動物模型中,AOM/DSS模型成瘤率高,周期短,最為常用。第三部分研究建立的AOM/DSS小鼠模型,作為結(jié)直腸炎癌轉(zhuǎn)化的動物模型,進行了AOM/DSS小鼠腫瘤的全基因組表達譜芯片實驗。結(jié)果發(fā)現(xiàn),小鼠經(jīng)歷了正�！坏湫驮錾蛳倭觥c癌的變化過程。經(jīng)過3個周期的DSS處理后,小鼠均生長了腫瘤。取不同處理周期的小鼠進行對比,發(fā)現(xiàn)隨著時間的推移,以及DSS處理周期的疊加,除Tgfb3基因外,小鼠的Il1a、Il1b、Il6、Il23a、Nfkb2、Tgfb1、 Ptgs2幾個基因均為高表達,且高表達趨勢大致持續(xù)升高,與人類腸癌的8個基因的表達趨勢相同,而Tgfb3的表達下降�？偨Y(jié)第一部分、第二部分及第三部分研究的結(jié)果,我們認為人類結(jié)直腸癌是一類具有異質(zhì)性的疾病,根據(jù)基因表達可進行進一步分子分型；無論在TCGA數(shù)據(jù)庫,或中國人腸癌中,炎癥亞型占比例相近,均為15%左右；炎癥型腸癌表現(xiàn)為IL1A、IL1B、IL6、IL23A、NFKB2、TGFB1、TGFB3、PTGS28個基因表達的升高；AOM/DSS小鼠模型的8個基因表達變化與人類炎癥型腸癌相近,可作為炎-癌轉(zhuǎn)化模型用于炎癥型腸癌的研究。AOM/DSS模型是否可應(yīng)用于其他類型的腸癌,尚需進一步研究。
[Abstract]:Colorectal cancer is one of the most common malignant tumors, seriously endangering human life and health. According to gene expression, colorectal cancer can be divided into five subtypes. One of them is inflammatory bowel cancer. In this study, bioinformatics was used to observe the expression of related inflammatory factors in human inflammatory colorectal cancer, and the mouse model of colitis associated colon cancer was established, and the gene expression data of the mouse model of inflammatory carcinoma transformation were obtained. The expression of related inflammatory factors in animal model was preliminarily verified and compared with that of human inflammatory bowel cancer. Molecular typing of colorectal cancer is the focus and focus of clinical research recently. More and more researchers pay attention to the study of inflammation and cancer transformation. A large number of studies have suggested and confirmed the process of inflammation into tumors, but not all tumors are derived from inflammation. This study focused only on changes in gene expression of several inflammatory factors in inflammatory bowel cancer. In this part, the genomic data of human colorectal cancer patients and adjacent tissues downloaded from TCGA database were used. Using bioinformatics, colorectal cancer was classified into five categories, including inflammatory colorectal cancer, and ILIA,IL1B,IL6,IL23A, was analyzed. Changes in several genes of NFKB2,TGFB1, TGFB3,PTGS2 in human inflammatory bowel cancer. The results showed that 98 cases of colorectal cancer were classified as inflammatory colorectal cancer in TCGA database, and all of the above 8 genes were overexpressed in inflammatory colorectal cancer. (part 2) the source of TCGA database samples is affected by region, race and other factors, but the results of clinical research are different according to different genetic background and population in different regions. In this part, 10 out of 67 patients were clustered into inflammatory bowel cancer by bioinformatics, and ILIA,IL1B,IL6,IL23A,NFKB2,TGFB1,TGFB3, was analyzed. The changes of several genes of PTGS2 in human inflammatory colorectal cancer were found to be highly expressed, and the change trend was consistent with the results of TCGA database. Animal models play an irreplaceable role in the study of the pathological mechanism of disease. In the animal model of inflammatory-associated bowel cancer, AOM/DSS model is the most commonly used model with high tumorigenesis rate and short cycle. In the third part, the AOM/DSS mouse model was established as an animal model of colorectal carcinoma transformation, and the whole genome expression profile of AOM/DSS mouse tumor was tested by microarray. The results showed that the mice experienced normal dysplasia or adenomatous carcinoma. After three cycles of DSS treatment, all mice grew tumor. The results showed that with the passage of time and the superposition of DSS treatment cycle, several genes of Il1a,Il1b,Il6,Il23a,Nfkb2,Tgfb1, Ptgs2 in mice were highly expressed except for Tgfb3 gene. The expression trend of high expression was similar to that of 8 genes in colorectal cancer, but the expression of Tgfb3 was decreased. Summarizing the results of the first part, the second part and the third part, we think that human colorectal cancer is a kind of heterogeneous disease, which can be further classified according to gene expression. The proportion of inflammatory subtypes was about 15% in both TCGA database and Chinese colorectal cancer, and the expression of IL1A,IL1B,IL6,IL23A,NFKB2,TGFB1,TGFB3,PTGS28 gene was increased in inflammatory colorectal cancer. The expression changes of 8 genes in AOM/DSS mouse model are similar to those in human inflammatory bowel cancer model, which can be used as an inflammatory carcinoma transformation model. Whether the AOM/DSS model can be applied to other types of colorectal cancer needs further study.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R735.3

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相關(guān)期刊論文 前2條

1 Cristina-Sorina Cǎanǎ;Ioana Berindan Neagoe;Vasile Cozma;Cristian Magdas;Flaviu Tǎbǎan;Dan Lucian Dumitrasu;;Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease[J];World Journal of Gastroenterology;2015年19期

2 Tae-Min Kim;Sug-Hyung Lee;Yeun-Jun Chung;;Clinical applications of next-generation sequencing in colorectal cancers[J];World Journal of Gastroenterology;2013年40期

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本文編號：2331492