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

2025 · doi:10.1101/2025.06.25.661448
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Intestinal epithelial C/EBPβ deficiency reduces colitis-associated tumorigenesis by impairing neutrophil infiltration via the CXCL1/2/5-CXCR2 pathway.

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The study investigated how dysregulated transcription factors connect chronic inflammation to colitis-associated colorectal cancer (CAC) by integrating microarray and transcriptome sequencing datasets from ulcerative colitis (UC), CAC, and colorectal cancer (CRC) patient samples. The authors identified C/EBPβ as a key regulator whose elevated intestinal expression inversely correlated with survival, and in AOM/DSS mouse CAC models intestinal epithelial C/EBPβ increased during tumor progression, matching greater tumor burden and neutrophil infiltration. Intestinal epithelial–specific Cebpb deletion reduced neutrophil recruitment and tumor growth, which the authors mechanistically linked to transcriptional activation of CXCR2 ligands (CXCL1, CXCL2, and CXCL5); pharmacological CXCR2 inhibition produced similar anti-tumor effects. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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/EBPβ 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/EBPβ is upregulated during tumor progression, correlating with exacerbated tumor burden and neutrophil infiltration. Mice with intestinal epithelial-specific Cebpb deletion ( Cebpb ΔIEC ) show resistance to carcinogenesis, accompanied by reduced neutrophil infiltration and tumor growth. Mechanistically, C/EBPβ transcriptionally activates CXCR2 ligands (CXCL1, CXCL2, and CXCL5) to drive neutrophil recruitment. Pharmacological inhibition of CXCR2 phenocopies the anti-tumor effects of Cebpb ΔIEC deletion, further validating this axis as a therapeutic target. Correlation analysis in patient tissues confirms positive relationships between C/EBPβ, CXCR2 ligands, and neutrophil infiltration, suggesting that targeting the C/EBPβ-CXCL1/2/5-CXCR2 axis may offer a novel strategy for CAC treatment.
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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/EBPβ 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/EBPβ is upregulated during tumor progression, correlating with exacerbated tumor burden and neutrophil infiltration. Mice with intestinal epithelial-specific Cebpb deletion (CebpbΔIEC) show resistance to carcinogenesis, accompanied by reduced neutrophil infiltration and tumor growth. Mechanistically, C/EBPβ transcriptionally activates CXCR2 ligands (CXCL1, CXCL2, and CXCL5) to drive neutrophil recruitment. Pharmacological inhibition of CXCR2 phenocopies the anti-tumor effects of CebpbΔIEC deletion, further validating this axis as a therapeutic target. Correlation analysis in patient tissues confirms positive relationships between C/EBPβ, CXCR2 ligands, and neutrophil infiltration, suggesting that targeting the C/EBPβ-CXCL1/2/5-CXCR2 axis may offer a novel strategy for CAC treatment. Competing Interest Statement The authors have declared no competing interest.

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