APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.
Publication/Presentation Date
5-3-2020
Abstract
Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis.
Volume
21
Issue
5
First Page
441
Last Page
451
ISSN
1555-8576
Published In/Presented At
Blomain, E. S., Rappaport, J. A., Pattison, A. M., Bashir, B., Caparosa, E., Stem, J., Snook, A. E., & Waldman, S. A. (2020). APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis. Cancer biology & therapy, 21(5), 441–451. https://doi.org/10.1080/15384047.2020.1721262
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
32037952
Department(s)
Administration and Leadership
Document Type
Article