Intestinal epithelium-derived BATF3 promotes colitis-associated colon cancer through facilitating CXCL5-mediated...

Inflammation is a critical player in the development and progression of colon cancer. Basic leucine zipper transcription factor ATF-like 3 (BATF3) plays an important role in infection and tumor immunity through regulating the development of conventional type 1 dendritic cells (cDC1s). However, the function of BATF3 in colitis and colitis-associated colon cancer (CAC) remains unclear. Here, BATF3 wild-type and knockout mice were used to construct an AOM/DSS-induced CAC model. In addition, DSS-induced chronic colitis, bone marrow cross-transfusion (BMT), neutrophil knockout, and other animal models were used for in-depth research. We found that BATF3 deficiency in intestinal epithelial cells rather than in cDC1s inhibited CAC, which was depended on inflammatory stimulation. Mechanistically, BATF3 directly promoted transcription of CXCL5 by forming a heterodimer with JunD, and accelerated the recruitment of neutrophils through the CXCL5-CXCR2 axis, ultimately increasing the occurrence and development of CAC. Tissue microarray and TCGA data also indicated that high expression of BATF3 was positively correlated with poor prognosis of colorectal cancer and other inflammation-related tumors. In summary, our results demonstrate that intestinal epithelial-derived BATF3 relies on inflammatory stimulation to promote CAC, and BATF3 is expected to be a novel diagnostic indicator for colitis and CAC.