The cGAS-STING signaling pathway mediates pyroptosis in colonic epithelial cells and accelerates the progression of CAC.

Abstract

OBJECTIVE: Colitis-associated cancer (CAC) is a minor subtype of CRC, accounting for 2% of CRC cases. It is also one of the most common and severe complications in patients with chronic IBD. The exact pathogenic mechanisms of CAC remain unclear. Therefore, actively investigating the pathogenesis of CAC and developing novel therapeutic strategies are of great significance for its prevention and treatment. METHODS: The mouse model of UC and CAC was induced using DSS and AOM stimulation. The model was validated through H&E staining, Masson, AB-PAS staining, and ELISA assays. Additionally, the expression levels of key molecules, including cGAS and STING, were examined in model mice using qRT-PCR and immunohistochemistry. Later, based on the mouse CAC model, STING inhibitors and agonists were administered in combination with H&E staining, Masson, AB-PAS staining, and ELISA assays to explore the impact of key molecular expression levels on CAC progression in mice. Finally, in a mouse UC organoid model, STING agonists were used in combination with NLRP3 inhibitor. WB, CCK8, immunofluorescence staining, and intestinal permeability tests were employed to investigate the regulatory mechanisms of pyroptosis in CAC development. RESULTS: DSS and AOM stimulation successfully induced the mouse UC and CAC model. Key proteins of the cGAS-STING pathway, including cGAS, p65, and IFN-I, were significantly upregulated in the mouse UC and CAC model. The STING agonist SR-717 markedly increased the expression of cGAS-STING pathway-related genes, such as cGAS, STING, p65, and IFN-I, exacerbating pathological features and serum inflammatory cytokine levels in the colonic cancer model. It also significantly upregulated pyroptosis marker proteins pro-caspase-1, GSDMD-N, and NLRP3, whereas the STING inhibitor H-151 effectively suppressed these effects. The NLRP3 inhibitor INF195 enhanced the proliferative capacity, membrane integrity, and intestinal barrier function of the mouse colon organoid model, providing partial protective effects. Meanwhile, the STING agonist SR-717 partially reversed the effects of INF195. CONCLUSION: The cGAS-STING signaling pathway accelerates the progression of CAC by promoting pyroptosis in colonic epithelial cells through NLRP3/caspase-1 mediation.