炎症型肠癌及炎癌转化模型中基因表达变化的初步研究
发布时间：2018-11-14 14:55
【摘要】：结直肠癌是最常见的恶性肿瘤之一,严重危害人类生命健康。根据基因表达情况,结直肠癌可分为5种亚型。其中之一为炎症型肠癌。本研究利用生物信息学方法观察了相关炎症因子在人类炎症型肠癌的表达变化,并建立了结肠炎相关结肠癌的小鼠模型,获得了炎癌转化小鼠模型的基因表达数据,并初步验证了相关炎症因子在动物模型中的表达变化,与人类炎症型肠癌进行了对比。(第一部分)结直肠癌的分子分型是近来临床关注和研究的重点和热点。而炎癌转化研究也越来越多地被研究者所关注。大量研究提示并证实了炎症转化为肿瘤的过程的存在,但并非所有的肿瘤都由炎症转化而来。本研究仅关注炎症型肠癌的若干炎症因子基因表达变化。本部分研究使用TCGA数据库下载的人类结直肠癌患者及癌旁组织的基因组数据,使用生物信息学方法,将结直肠癌分为包括炎症型肠癌在内的5类,并分析了ILIA、IL1B、IL6、IL23A、NFKB2、TGFB1、 TGFB3、PTGS2几个基因在人类炎症型肠癌的变化情况。结果发现在TCGA数据库647例肠癌中,98例肠癌被分型为炎症型肠癌,在炎症型肠癌中,上述8个基因均呈高表达。(第二部分)TCGA数据库的样本来源受地域、人种等因素影响,而针对不同遗传背景、不同地区人群,临床研究所取得的结果不尽相同。本部分研究使用我院临床患者的样本,使用生物信息学方法,将67例患者中的10例聚类至炎症型肠癌,并分析了ILIA、IL1B、IL6、IL23A、NFKB2、TGFB1、TGFB3、PTGS2几个基因在人类炎症型肠癌的变化情况,结果发现,上述几个基因均呈高表达,且变化趋势与TCGA数据库的结果一致。(第三部分)动物模型在疾病的病理机制的研究中一直有着无可替代的作用。在炎症相关性肠癌的动物模型中,AOM/DSS模型成瘤率高,周期短,最为常用。第三部分研究建立的AOM/DSS小鼠模型,作为结直肠炎癌转化的动物模型,进行了AOM/DSS小鼠肿瘤的全基因组表达谱芯片实验。结果发现,小鼠经历了正常→不典型增生或腺瘤→肠癌的变化过程。经过3个周期的DSS处理后,小鼠均生长了肿瘤。取不同处理周期的小鼠进行对比,发现随着时间的推移,以及DSS处理周期的叠加,除Tgfb3基因外,小鼠的Il1a、Il1b、Il6、Il23a、Nfkb2、Tgfb1、 Ptgs2几个基因均为高表达,且高表达趋势大致持续升高,与人类肠癌的8个基因的表达趋势相同,而Tgfb3的表达下降。总结第一部分、第二部分及第三部分研究的结果,我们认为人类结直肠癌是一类具有异质性的疾病,根据基因表达可进行进一步分子分型；无论在TCGA数据库,或中国人肠癌中,炎症亚型占比例相近,均为15%左右；炎症型肠癌表现为IL1A、IL1B、IL6、IL23A、NFKB2、TGFB1、TGFB3、PTGS28个基因表达的升高；AOM/DSS小鼠模型的8个基因表达变化与人类炎症型肠癌相近,可作为炎-癌转化模型用于炎症型肠癌的研究。AOM/DSS模型是否可应用于其他类型的肠癌,尚需进一步研究。
[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.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.3
本文编号：2331492
[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.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.3
【参考文献】
相关期刊论文 前2条
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
，本文编号：2331492
本文链接：https://www.wllwen.com/yixuelunwen/zlx/2331492.html
