Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.

Epigenetic modifications play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) by mediating gene-environment interactions. We previously showed that UHRF1, a central regulator of DNA methylation, contributes to cancer progression; however, its function in IBD remains poorly understood. Here, we revealed that UHRF1 was frequently reduced in inflamed tissues of patients with IBD and that its deficiency exacerbated intestinal epithelial cell (IEC) damage. Through a multilevel approach incorporating human cell models and an intestinal epithelial-specific Uhrf1 -KO mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoted its methylation, and led to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP/PKA/CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent proinflammatory responses, which compromised intestinal epithelial barrier integrity. Furthermore, we identified miR-141 as a negative regulator of NPY1R, highlighting its potential as a therapeutic agent. Collectively, our results identified the UHRF1/NPY1R regulatory axis as a critical epigenetic mechanism in intestinal inflammation and underscored its dual promise for IBD diagnostics and therapy.