• The brown module correlated positively with CRC in WGCNA.• CRC tissues showed lower GUCA2B expression by RT-qPCR.• GUCA2B is a key gene among DEGs.• The top miRNAs associated with GUCA2B were found.• According to ROC studies, GUCA2B has a strong diagnostic performance for CRC. Here, GUCA2B is linked to colorectal carcinoma.