APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment
10.16016/j.2097-0927.202404020
- VernacularTitle:APE1通过免疫抑制性肿瘤微环境介导结肠炎相关结直肠癌的发生发展
- Author:
Tianyi CHEN
1
;
Chaofan LI
;
Lingbo BAO
;
Qian CHEN
;
Nana HU
;
Yuxin YANG
;
Lei ZHANG
;
Dong WANG
Author Information
1. 400042 重庆,陆军特色医学中心肿瘤中心
- Keywords:
colitis-associated colorectal cancer;
inflammatory bowel diseases;
apurinic/apyrimidinic endonuclease 1;
polymorphonuclear myeloid-derived suppressor cells;
colorectal cancer;
tumor microenvironment
- From:
Journal of Army Medical University
2024;46(16):1825-1837
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the regulatory mechanism of apurnic/apyrimidinic endonuclease 1(APE1)in the transformation of chronic intestinal inflammation to colitis-associated colorectal cancer(CAC).Methods C64S mutant(APE1C64S)mice and APE1 wild type(APE1WT)mice were randomly divided into experimental group and control group.In vivo CAC model was established by azoxymethane(AOM)and dextran sulfate sodium salt(DSS)solution.Immunohistochemistry(IHC)and multiple IHC(mIHC)assays were used to observe the expression of APE1 and immune cell infiltration in colon tissues of each group.A mouse colon cancer cell line MC38 with stable knockdown of APE1 was constructed by lentivirus transfection,and subcutaneous tumor bearing experiments were performed in APE1WT and APE1C64S mice to confirm that tumor cell-derived APE1 caused immunosuppressive tumor microenvironment.The expression of APE1 and CXCL1[chemokine(C-X-C motif)ligand 1]and the infiltration of immune cells in tumor-bearing specimens were analyzed by IHC and mIHC assays.The tumor specimens of a 28-year-old female patient with CAC from Army Medical Center of PLA were analyzed for the expression of APE1 and CXCL1 and the infiltration of immune cells in the tumor and adjacent inflammatory tissues by IHC and mIHC assays.Results Compared with the control group and APE1WT erperimental group,APE1C64S erperimental group had significantly reduced disease activity index and tumor formation,polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)infiltration,and CD4+and CD8+T cells(P＜0.05).No significant differences were observed in tumor growth and immune cells between APE1WT and APE 1C64S mice bearing subcutaneous tumors.However,in the tumor-bearing experiment using tumor cells with knockdown of APE1,the tumor growth was significantly lower and the number of infiltrated PMN-MDSCs was reduced,while those of CD4+and CD8+T cells were significantly increased(P＜0.05).Furthermore,high expression of APE1 and increased infiltration of PMN-MDSCs were found in the tumor tissues of the young CAC patient,and CD8+T cells were significantly reduced in the tumor tissues compared with the inflammatory tissues(P＜0.05).Conclusion APE1-redox in tumor cells can promote the infiltration of PMN-MDSCs and reduce the number of T cells,thereby forming an immunosuppressive tumor microenvironment and mediating the occurrence and development of CAC.
