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.

Multidrug resistance (MDR) remains a significant barrier to effective chemotherapy and results in a poor prognosis for gastric cancer (GC). Exploring the mechanism of MDR is highly important for identifying biomarkers for MDR and developing new treatment strategies. In this study, integrative analyses of multiomics and bioinformatics data were combined with experimental validation to explore the mechanism of MDR in GC. We found that phosphoglycerate dehydrogenase (PHGDH), the key rate-limiting enzyme in the serine synthesis pathway, was significantly upregulated in MDR GC cells. PHGDH was found to perform a noncanonical function to promote MDR by activating the Wnt/β-catenin signaling pathway, and this effect is mediated by transcription factor 7-like 2 (TCF7L2), a pivotal co-activator of β-catenin in the Wnt pathway. Specifically, PHGDH stabilizes TCF7L2 mRNA by interacting with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), a key m6A reader, in an m6A-dependent manner, thereby increasing the expression of TCF7L2. Moreover, TCF7L2 binds to the promoter of PHGDH and regulates its expression, which forms a positive feedback loop. This PHGDH/IGF2BP1–TCF7L2 loop contributes to GC MDR and is correlated with a poor prognosis of GC patients.