| BackgroundColorectal cancer(CRC)is one of the most common and high-incidence malignant tumors in the world.According to the World Health Organization,there are 1,931,590 new cases of colorectal cancer worldwide in 2020,accounting for 10%of all malignant tumors and ranking third.And the number of deaths is 935,173 accounting for 9.4%of all malignancies and ranking second.Ulcerative colitis is a representative of Inflammatory bowel disease(IBD),which is closely related to colorectal cancer.In the process of tumorigenesis of the Colitis-Associated colorectal cancer,long-term and complex interactions have occurred between intestinal epithelial cells and inflammatory environment,and multiple inflammatory signaling pathways are activated,leading to the occurrence of colorectal cancer,in which inflammatory cells and a variety of inflammatory factors play an important role in tumorigenesis.Interleukin 11(IL-11)is a pleiotropic cytokine with a wide range of sources and can be detected in many types of cells.However,how IL-11 plays its role in tumorigenesis and whether it mediates the tumor immune escape have not been revealed.Therefore,in this project,we will explore the biological function of IL-11 in the transformation from enteritis to colorectal cancer and its mechanism of promoting immune escape,through cell and organoid experiments and mice model.Methods1.Human UC,CRC and normal intestinal tissues are collected to detect the expression of IL-11;The enteritis associate colorectal cancer model is constructed by AOM/DSS in Wild Type(WT)and IL11 gene knockout(IL11-/-)mice.Intestinal tumor formation is observed by colonoscopy,the number and size of tumors are counted.2.Colitis is induced in WT and IL11-/-mice by DSS,and is monitored by colonoscopy,and inflammation score is evaluated.The expression of IL-11 and MHC-Ⅰ molecules in intestinal mucosa is detected by RT-Q-PCR.3.Mice and human large intestine are cultured and stimulated with IL-11 and IFN-γ to observe the activation of STAT1 and the expression of MHC-I molecules.The expression of MHC-I molecules in intestinal inflammatory mucosa of IL11-/mice is detected by RT-Q-PCR.CT26 cells are subcutaneously implanted and treated with IL-11 mutant protein.Tumor growth is observed.The infiltration of CD8+T cells and the expression of PD-L1 in the tumor are observed by immunofluorescence.Results1.The expression of IL-11 in UC and CRC tissue is significantly higher than that in normal colon tissue;Compared with WT mice,we found that the number and diameter of intestinal tumors in IL11-/-mice are reduced and the number of infiltrating T cells in tumors is increased.2.IL-11 expression is significantly increased during colitis,and is negatively correlated with the expression of MHC-I molecules;GEO database analyzed the relationship between IL-11 and MHC-I molecules,and the same result is obtained.3.Mouse and human colorectal organoid are isolated and cultured,and IL-11 inhibited the stimulation of IFN-y on organoids,resulting in phosphorylation of STAT1 and down-regulation of IRF1 expression;After IL-11 knockout,MHC-I molecules in intestinal inflammatory tissues of IL11-/-mice is significantly upregulated;After treatment with the IL-11 mutant protein,the growth rate of subcutaneous tumors in mice is significantly slowed down,the number of infiltrated CD8+T cells is significantly increased,and the expression of PD-L1 is significantly upregulated.ConclusionIn the process of inflammation related tumorigenesis,IL-11 reduces the expression of MHC-I molecules,leading to the inability of tumor antigen presentation,and CD8+T cell can not effectively recognize abnormally proliferating cells,resulting in tumor immune escape. |
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