APC-ß-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.
Cancer Biol Ther
; 21(5): 441-451, 2020 05 03.
Article
in En
| MEDLINE
| ID: mdl-32037952
ABSTRACT
Sporadic colorectal cancer initiates with mutations in APC or its degradation target ß-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-ß-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-ß-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 ß-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Adenomatous Polyposis Coli Protein
/
Natriuretic Peptides
/
Beta Catenin
/
TCF Transcription Factors
/
Receptors, Enterotoxin
/
Gastrointestinal Hormones
/
Intestinal Mucosa
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Biol Ther
Journal subject:
NEOPLASIAS
/
TERAPEUTICA
Year:
2020
Document type:
Article
Affiliation country:
United States