CLDN8 protects against colitis-associated colorectal cancer by regulating intestinal mucosal homeostasis and IL-6-associated proliferation

Colitis-associated cancer (CAC) is a lethal complication of inflammatory bowel disease (IBD). The tight junction member Claudin-8 (CLDN8) is downregulated in IBD, while its potential role in CAC has not yet been characterized. Our objective was to identify the protective role of CLDN8 in intestinal mucosal homeostasis against CAC development. CLDN8 expression was examined in tumor tissues from ulcerative colitis-associated cancer and colorectal cancer (CRC) patients, and in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC mouse models. RNA-seq analysis, mucosal permeability test, and fecal 16S rRNA gene sequencing were performed in Cldn8 intestinal epithelial-specific knockout mice with induced CAC. Enriched differential pathways from the RNA-seq analysis were examined by western blotting and verified in vitro. CLDN8 expression in tumor tissues of patients with CRC, CAC, and AOM/DSS mice was downregulated compared to that in para-cancer tissues. Cldn8 depletion increased the tumor number and their decreased formation time in CAC mouse models. Knockout of Cldn8 caused a leaky intestinal barrier, increased bacteria invading submucosa and tumor, and changed intestinal microbiota β diversity. Moreover, Faecalibaculum , a reported cancer suppressor, significantly decreased. CLDN8 deficiency significantly increased IL-6 expression in the CAC model. RNA-seq and western blot analyses revealed significant activation of the STAT3 pathway. Further, CLDN8 deficiency enhances IL-6-induced epithelial proliferation, at least in part through STAT3 signaling. Our data suggest that CLDN8 deficiency disrupts intestinal barrier integrity, which may be associated with gut microbiota dysbiosis and CAC progression, potentially via altered IL-6/STAT3 signaling.