APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis

Area of Science:

• Gastroenterology
• Oncology
• Molecular Biology

Background:

• Sporadic colorectal cancer (CRC) is driven by mutations in APC or β-catenin, leading to TCF-dependent transcription and tumor growth.
• The GUCY2C receptor and its ligand, guanylin, normally maintain intestinal homeostasis and oppose tumorigenesis.

Purpose of the Study:

• To investigate the role of guanylin hormone and GUCY2C receptor expression in the early stages of APC-dependent colorectal cancer.
• To elucidate the molecular mechanisms by which APC mutations affect guanylin and GUCY2C signaling in tumorigenesis.

Main Methods:

• Analysis of guanylin and GUCY2C expression in human and mouse APC-dependent colorectal tumors.
• Investigation of transcriptional regulation by mutant APC-β-catenin-TCF complexes.
• Assessment of GUCY2C signaling dysregulation in tumor initiation and progression.

Main Results:

• Guanylin hormone expression, but not GUCY2C receptor expression, is lost early in APC-dependent colorectal tumors.
• Mutant APC-β-catenin-TCF transcriptional programs repress guanylin expression, silencing GUCY2C signaling.
• Loss of guanylin-GUCY2C signaling contributes to the dysregulation of intestinal homeostasis and promotes tumor progression.

Conclusions:

• APC-driven colorectal tumorigenesis involves the transcriptional silencing of the guanylin hormone, leading to loss of GUCY2C signaling.
• Guanylin hormone loss is an early event in colorectal cancer initiation, distinct from irreversible APC/β-catenin mutations.
• Therapeutic restoration of guanylin hormone and GUCY2C signaling presents a potential strategy for colorectal cancer prevention.