Deficiency in Epithelium RAD50 Aggravates UC via IL-6-Mediated JAK1/2-STAT3 Signaling and Promotes Development of Colitis-Associated Cancer in Mice - Report - MDSpire
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Deficiency in Epithelium RAD50 Aggravates UC via IL-6-Mediated JAK1/2-STAT3 Signaling and Promotes Development of Colitis-Associated Cancer in Mice
Loss of Epithelial RAD50 Exacerbates Ulcerative Colitis and Promotes Colitis-Associated Cancer
Overview
RAD50 expression is reduced in ulcerative colitis (UC) and colitis-associated cancer (CAC), leading to increased DNA double-strand breaks and activation of the IL-6-JAK1/2-STAT3 inflammatory pathway. Mice lacking epithelial RAD50 exhibit worsened colitis and enhanced tumor development, which can be alleviated by STAT3 inhibition.
Background
Ulcerative colitis is a chronic inflammatory bowel disease that increases the risk of developing colitis-associated cancer. DNA double-strand breaks (DSBs) are highly cytotoxic lesions implicated in IBD and CAC pathogenesis. RAD50 is a key sensor of DSBs involved in DNA repair and immune regulation. The IL-6-JAK-STAT3 signaling pathway is known to promote inflammation and tumorigenesis in the gastrointestinal tract. Understanding the role of RAD50 in modulating this pathway may reveal novel therapeutic targets for UC and CAC.
Data Highlights
Parameter
Observation
RAD50 expression
Reduced in human IBD and CAC tissues and mouse models
γ-H2AX (DSB marker)
Increased in colitis and CAC models
RAD50IEC-KO mice sensitivity
Increased susceptibility to DSS-induced acute and chronic colitis
IL-6-JAK1/2-STAT3 pathway
Activated in RAD50-deficient epithelial cells
Effect of STAT3 inhibition
Relieved colitis symptoms in RAD50IEC-KO mice
Tumor development
Enhanced in RAD50IEC-KO mice after AOM-DSS treatment
Key Findings
RAD50 expression is decreased in intestinal epithelium of patients with IBD and CAC as well as in corresponding mouse models.
Loss of epithelial RAD50 sensitizes mice to chemically induced colitis, resulting in more severe inflammation and DNA damage.
RAD50 directly interacts with STAT3, inhibiting its phosphorylation and disrupting the IL-6-JAK1/2-STAT3-IL-6 inflammatory feed-forward loop.
Pharmacological inhibition of STAT3 ameliorates colitis severity in RAD50-deficient mice.
RAD50 deficiency leads to increased cell proliferation and persistent DNA damage, promoting colitis-associated tumorigenesis in murine models.
Enhancing RAD50 levels in colon tissues may represent a promising therapeutic strategy for UC and CAC.
Clinical Implications
These findings highlight RAD50 as a critical modulator of intestinal inflammation and tumorigenesis through regulation of the IL-6-STAT3 pathway. Therapeutic strategies aimed at restoring RAD50 function or targeting STAT3 signaling may improve outcomes in patients with ulcerative colitis and reduce the risk of colitis-associated cancer development.
Conclusion
Epithelial RAD50 plays a protective role against ulcerative colitis progression and colitis-associated cancer by suppressing IL-6-driven STAT3 activation and maintaining genomic integrity. Targeting this pathway offers potential for novel interventions in IBD and CAC management.
References
Original Article 2024 -- Loss of Epithelium RAD50 Exacerbates Ulcerative Colitis through IL-6-Driven JAK1/2-STAT3 Pathway and Facilitates Colitis-Associated Cancer Development in Murine Models
