Deficiency in Epithelium RAD50 Aggravates UC via IL-6-Mediated JAK1/2-STAT3 Signaling and Promotes Development of Colitis-Associated Cancer in Mice

Abstract

BACKGROUND: Ulcerative colitis (UC) is one of the most important risk factors for developing colitis-associated cancer (CAC). Persistent DNA damage increases CAC risk and has been observed in patients with UC. We aimed to identify the regulatory role of RAD50, a DNA double-strand breaks (DSBs) sensor, in UC progression to CAC. METHODS: DSBs and RAD50 expression in inflammatory bowel disease (IBD) and CAC cell and mouse models were assessed. Mice with intestinal epithelial RAD50 deletion (RAD50IEC-KO) were used to examine the role of RAD50 in colitis and CAC. RESULTS: Along with the increased γ-H2AX expression in colitis and CAC models, RAD50 expression was reduced in human IBD and CAC as well as in mouse models. Furthermore, RAD50IEC-KO sensitizes mice to dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis. RNA-seq analyses revealed that RAD50IEC-KO activated the cytokine-cytokine receptor response, which was amplified through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. RAD50 directly interacts with STAT3 and subsequently inhibits its phosphorylation, which may disrupt the IL-6-JAK1/2-STAT3-IL-6 feed-forward loop. Pharmacological STAT3 inhibition relieves colitis in RAD50IEC-KO mice. Severe DSBs, increased cell proliferation, and extended inflammatory response were identified in RAD50-deficient cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice. CONCLUSIONS: RAD50 exerts anti-IL-6-related inflammatory effects in colitis and suppresses CAC. Increasing RAD50 level in colon tissues may be promising for treating patients with UC and CAC.