• In both human and mouse APC-dependent tumors, the loss of guanylin hormone expression occurs at the initial stages of transformation, while the GUCY2C receptor remains unaffected.• Broadening the mechanistic framework for colorectal cancer from being solely characterized by irrevocable mutations in APC and β-catenin, to encompass the loss of guanylin hormone, whose restoration and revival of GUCY2C signaling might hold the potential to deter tumorigenesis. This evidence concerns the gene GUCY2C and colorectal cancer.