Clinical importance of the interactions between the TGF-β1/SMAD and NF-κB pathways in colorectal cancer and the study of the synergistic regulatory mechanism of the STAT3-mediated pathway.

This study aimed to explore the clinical significance and potential mechanisms of the transforming growth factor- β1 (TGF-β1)/small mother against decapentaplegic (SMAD) and nuclear factor kappa B (NF-κB) pathways in colorectal cancer (CRC). Transcriptomic and clinical data of CRC patients were retrieved from TCGA and GEO databases, analyzed via TCGAbiolinks, GEPIA 2, KEGG, and GO. A total of 275 colon cancer and 92 rectal cancer samples were included. Results showed TβR2 and SMAD2 expression was significantly associated with CRC pathological stage ( P  < 0.05), while low TGF-β1, TβR1, and TβR2 expression correlated with longer disease-free survival (DFS, P  < 0.05). Pathway component correlations differed between normal and cancerous tissues; high co-expression of NF-κB1 and SMAD2 linked to longer DFS in rectal cancer ( P  < 0.05). Signal transducer and activator of transcription 3 (STAT3) strongly correlated with NF-κB1, SMAD2/4 (R = 0.7, 0.63, 0.65; P  < 0.001), and combinations of NF-κB1 with SMAD2/SMAD4 showed strong correlations with STAT3 (R = 0.73; P  < 0.001). NF-κB1 combined with SMAD2 has prognostic value for rectal cancer, and STAT3 may be a common upstream transcription factor regulating both pathways.