In our study, we showed that the expression of CTNNBIP1 and SERPINF1 was down‐regulated and the expression of LGR4 was up‐regulated in the HD and UA compared to the UAG, showing the adaptive response of the colorectal cancer cells to the 3DRMs that lacked matrix support and the efforts of improving the Wnt/β‐catenin signaling activity. This evidence concerns the gene LGR4 and colorectal cancer.