cGAS-STING Modulates the NF-κB Pathway to Influence the Occurrence of Ulcerative Colitis-Associated Colorectal Cancer.

backgroundUlcerative colitis (UC) is a well-established high-risk contributor for the pathogenesis of colitis-associated colorectal cancer (CAC), with patients exhibiting a markedly increased risk of CAC compared with the general population. However, the underlying mechanisms driving this transformation are incompletely elucidated.

methodsThe expression of key molecules in the cGAS-STING/NF-κB signaling pathway was detected via RT-qPCR and Western blot. Immunofluorescence staining was performed to assess the release of double-stranded DNA (dsDNA). Immunohistochemistry (IHC) was used to examine the expression of cGAS, STING, p-p65, Ki67, and Cleaved caspase-3. Colon crypt cells isolated from mice were utilized to establish an organoid model, through which organoid viability, morphology, inflammatory factor secretion, and p65 nuclear translocation were evaluated. Dextran sulfate sodium (DSS)-induced UC mouse model and azoxymethane (AOM)/DSS combined CAC mouse model were constructed. Disease activity index (DAI), colon length, and tumor number were recorded to evaluate disease progression and verify the in vivo function of the cGAS-STING pathway. Plasmid transfection and pathway inhibitors were applied to explore the specific mechanisms underlying the cGAS-STING pathway.

resultsCompared with the control group, the mRNA and protein levels of cGAS-STING/NF-κB pathway-related molecules were progressively elevated, while IκBα expression was reduced, accompanied by cytoplasmic dsDNA accumulation in colonic tissues of UC and CAC mice, indicating that this pathway was gradually activated during the progression from inflammation to tumorigenesis. In the colon organoid model, DSS treatment triggered activation of this pathway, resulting in structural destruction and enhanced secretion of inflammatory cytokines. The STING agonist SR-717 exacerbated these pathological changes and facilitated p65 nuclear translocation, whereas the STING inhibitor H-151 or cGAS knockdown alleviated tissue injury and suppressed p65 nuclear translocation. Mechanistic investigations revealed that the NF-κB inhibitor Bay11-7082 effectively abrogated the proinflammatory effects induced by SR-717. Consistent with in vitro findings, in vivo data from the CAC mouse model further demonstrated that SR-717 administration promoted tumor formation, as evidenced by upregulated expression of the proliferation marker Ki67 and downregulated expression of the apoptotic marker Cleaved caspase-3. Notably, co-treatment with Bay11-7082 reversed the tumor-promoting phenotypes driven by SR-717.

conclusionThis study suggests that the cGAS-STING signaling pathway plays an important promoting role in the malignant transformation from UC to CAC by activating NF-κB signaling, providing experimental evidence for elucidating the pathogenesis of CAC.