ZFP90 drives initiation of colitis-associated colorectal cancer using a microbiota-dependent strategy

Chronic inflammation and gut microbiota dysbiosis are risk factors for colorectal cancer. In clinical practice, inflammatory bowel disease (IBD) patients have a greatly increased risk of developing colitis associated colorectal cancer (CAC). However, the basis underlying the initiation of CAC remains to be explored. Systematic filtration through existing genome-wide association study (GWAS) and conditional deletion of Zfp90 in CAC mice model indicated that Zfp90 was a putative oncogene in CAC development. Strikingly, depletion of gut microbiota eliminated the tumorigenic effect of Zfp90 in CAC mice model. Moreover, fecal microbiota transplantation demonstrated Zfp90 promoted CAC depending on gut microbiota. Combining 16s rDNA sequencing in feces specimens from CAC mice model, we speculated that Prevotella copri-defined microbiota might mediate the oncogenic role of Zfp90 in the development of CAC. Mechanistic studies revealed Zfp90 accelerated CAC development through Tlr4-Pi3k-Akt-Nf-?b pathway. Our findings elucidated the crucial role of Zfp90-microbiota-Nf-?b axis in creating a tumor-promoting environment and suggested therapeutic targets for CAC prevention and treatment. Overall design: Examination of colon epithelium gene expression from two groups: (1) Zfp90fl/f with AOM-DSS treatment; (2) Zfp90?IEC with AOM-DSS treatment.