Deficiency in epithelium RAD50 aggravates UC via IL-6-mediated JAK1/2-STAT3 signaling and promotes development of colitis-associated cancer in mice.
J Crohns Colitis
; 2024 Aug 29.
Article
em En
| MEDLINE
| ID: mdl-39207300
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 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 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 RAD50 activated the cytokine-cytokine receptor response, which was amplified through the 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-deficienct cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice.CONCLUSION:
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
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Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Idioma:
En
Revista:
J Crohns Colitis
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China