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bioRxiv · 10.1101/2025.06.25.661448

Intestinal Epithelial C/EBPβ Deficiency Impairs Colitis-Associated Tumorigenesis by Disrupting CXCL1 /CXCL2/CXCL5-CXCR2-Mediated Neutrophil Infiltration

Li, M.·Wang, X.·Hu, W.·Cheng, X.·Sun, Q.·Wu, Y.·Huang, Z.·Chen, J.
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Abstract

Dysregulated transcription factors critically link chronic inflammation to oncogenesis in colitis-associated colorectal cancer (CAC), but their mechanistic roles remain incompletely understood. By integrating microarray and transcriptome sequencing data from ulcerative colitis (UC), colitis-associated cancer (CAC), and colorectal cancer (CRC) patients, we identify C/EBP{beta} as a key transcriptional regulator whose elevated expression inversely correlates with survival. In azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC models, intestinal epithelial C/EBP{beta} is upregulated during tumor progression, correlating with exacerbated tumor burden and neutrophil infiltration. Mice with intestinal epithelial-specific Cebpb deletion (Cebpb{Delta}IEC) show resistance to carcinogenesis, accompanied by reduced neutrophil infiltration and tumor growth. Mechanistically, C/EBP{beta} transcriptionally activates CXCR2 ligands (CXCL1, CXCL2, and CXCL5) to drive neutrophil recruitment. Pharmacological inhibition of CXCR2 phenocopies the anti-tumor effects of Cebpb{Delta}IEC deletion, further validating this axis as a therapeutic target. Correlation analysis in patient tissues confirms positive relationships between C/EBP{beta}, CXCR2 ligands, and neutrophil infiltration, suggesting that targeting the C/EBP{beta}-CXCL1/2/5-CXCR2 axis may offer a novel strategy for CAC treatment.

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Li, M., Wang, X., Hu, W., Cheng, X., Sun, Q., Wu, Y., Huang, Z., Chen, J.. 2025-06-27. Intestinal Epithelial C/EBPβ Deficiency Impairs Colitis-Associated Tumorigenesis by Disrupting CXCL1 /CXCL2/CXCL5-CXCR2-Mediated Neutrophil Infiltration. https://doi.org/10.1101/2025.06.25.661448

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