Disease- and Region-Specific Molecular Patterns Involving miRNAs and Associated Signalling Pathways and Epithelial Cell-Fate Responses in PSC-Associated Ulcerative Colitis

Abstract

Patients with primary sclerosing cholangitis-associated ulcerative colitis (PSC-UC) have an elevated risk of colorectal cancer compared with ulcerative colitis (UC), but the molecular mechanisms linking chronic inflammation to epithelial cell fate remain unclear. The present study investigated disease- and region-specific molecular patterns involving miRNAs and associated PI3K/AKT, STAT3, and NF-κB signalling pathways. miR-21, miR-181a, miR-181b, and key pathway components were analysed in paired ascending and sigmoid colon biopsies from patients with PSC, PSC-UC, UC, and controls. Functional effects were examined in HT-29 and NCM460D cells, and circulating miRNAs, including miR-155, were assessed. UC was characterised by marked miR-181a upregulation and PI3K/AKT activation, whereas PSC-UC showed reduced PDCD4, divergent p65 regulation, and altered miR-181a/miR-181b coordination. In NCM460D cells, miR-181a and miR-181b reduced viability, promoted apoptosis, impaired cell-cycle progression, and decreased PDCD4, p-AKT, and p-STAT3; miR-181b additionally reduced CYLD. Serum miR-155 was elevated in PSC-UC compared with UC and showed the strongest individual discriminatory capacity. Random forest analysis and an exploratory multivariable serum miRNA profile showed discriminatory potential. These findings support disease- and region-specific molecular patterns involving miRNAs and associated signalling pathways linked to epithelial cell-fate responses in PSC-UC and highlight molecular differences between PSC-UC and conventional UC.