Data Analysis Of Colitis-associated Carcinogenesis Mouse Model And Study On The Role Of LEF1/TCFs Members In The Process

Inflammatory bowel disease (IBD), a recurrent chronic inflammation, is one of the high risks of colorectal cancers (CRCs). The process of inflammation-to-cancer transition is quite complex and involves multiple pathways and molecules. However, the exact mechanism is not well studied. In the current study, we first established the colitis-associated colon cancer mouse model, obtained the whole genome expression profile, and conducted data analysis; besides, we investigated the expression of genes related to intestinal stem cell and its niche; at last, we focused on the different roles of LEF1/TCFs members during colitis-associated colorectal carcinogenesis and the possible mechanisms.(Part 1) The AOM-DSS mouse model is an important tool for the study of colitis-associated colonic carcinogenesis. However, there is little report about the molecular mechanism of the model. We established the AOM-DSS model and conducted whole genome expression profile. By comparative analysis of different groups of data, including tumor vs. normal group (AD3_VS_Con), tumor vs. para-tumor group (AD3_VS_AD3N), late stage vs. early stage group (AD3_VS_AD2), we found that there were always differenatial genes between different stages of the same region and between different regions of the same stage. Genes related to defense response, inflammatory response, transcription, cell proliferation and cell motion were upregulated in the process of colitis-to-cancer transition (CCT); while genes related to cell adhesion or drug metabolism were downregulated. Besides, some differential genes related to nervous system, metabolism pathways and other molecular mechanisms, which had not drawn enough attention, might involve in the malignant transformation of cell. All these provided us important theory evidence for the future study.(Part 2) The role of tumor microenvironment in tumorigenesis and development receives increasing attention and concern. The colon cancer stem cell and its microenvironment are the hotspot in recent studies. Substantial studies suggest that colon cancer stem cell is the origin of carcinogenesis, progression, metastasis and recurrence. So far, the corresponding mechanism research is still in its infancy. We compared the differential genes in the CCT process (AD3_VS_Con) with some datasets about stem cell and its niche to find out the related important molecular networks. Results showed that between the upregulated differential genes in the expression profile (AD3_VS_Con_up) and and the stem cell related genes, there were 8 common genes (Rrm2, Pole2, Cenpa, Mybl2, Tpx2, Dlgap5, Kif4, Ncapg2); while between the downregulated differential genes (AD3_VS_Con_dn) and differentiation related genes, there were 5 common genes (Mepla, Mylk, Plekhg6, Gdpd2, Ace). Abnormal expression of these genes was closely associated with colon cancer, other cancers or other gastrointestinal diseases. Between the genes in AD3_VS_Con_up and the signature genes of Lgr5-GFPhigh cells, there were 7 common genes, most of which were related to Wnt/p-catenin pathway, such as Apcddl, Axin2 and Lect2.(Part 3) Canonical Wnt/β-catenin pathway involves in both the self-renewal and tissue repair of the intestinal and the care ino genes is and progression of colorectal cancers (CRC). The LEF1/TCFs family of the pathway, which consists of LEF1, TCF1, TCF4 and TCF3, mediates the binding between β-catenin and DNA. It’s reported the four members play different roles in multiple processes. To investigate the role of the LEF1/TCFs family members in colitis-associated carcinogenesis, we carried out the study. In the whole genome expression profiles of the colonic tissues, we found that LEF1 and TCF1 were upregulated in the process while TCF3 and TCF4 were downregulated. Some Wnt/β-catenin target genes also changed oppositely. The results were confirmed both in mouse tissues and human samples. In the mechanism study, we found that TCF1 and LEF1 might involve in the regulation of cancer stem cell function through upregulation of LGR5 and CD44. And the differential expression of LEF1/TCFs members might result from the regulation of different miRNAs.To sum up, the study suggest that in the CCT process, genes related to defense response, inflammatory response, transcription, cell proliferation and cell motion were upregulated, while genes related to cell adhesion and drug metabolism were downregulated; some genes related to stem cell and its microenvironment might play important roles in the process. The LEF1/TCFs family members were differentially expressed in the process, which might result from the regulation of different miRNAs. TCF1 and LEF1 might involve in the regulation of cancer stem cell function through regulation of LGR5 and CD44.