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APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis
- Source :
- Cancer Biology & Therapy, article-version (VoR) Version of Record
- Publication Year :
- 2020
- Publisher :
- Informa UK Limited, 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
- Subjects :
- 0301 basic medicine
Cancer Research
β catenin tcf signaling
Colorectal cancer
Guanylin
Adenomatous Polyposis Coli Protein
Receptors, Enterotoxin
colorectal cancer
medicine.disease_cause
law.invention
Gastrointestinal Hormones
Mice
03 medical and health sciences
0302 clinical medicine
Transcription (biology)
law
Cell Line, Tumor
Databases, Genetic
Paracrine Communication
medicine
Transcriptional regulation
chemoprevention
Animals
Humans
transcriptional regulation
Genes, Tumor Suppressor
Intestinal Mucosa
guanylyl cyclase C
Natriuretic Peptides
beta Catenin
Mice, Knockout
Pharmacology
Chemistry
GUCA2A
Guanylate cyclase 2C
medicine.disease
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Suppressor
Colorectal Neoplasms
TCF Transcription Factors
Carcinogenesis
Research Article
Research Paper
Signal Transduction
Subjects
Details
- ISSN :
- 15558576 and 15384047
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Cancer Biology & Therapy
- Accession number :
- edsair.doi.dedup.....382d7faa43164968ecd08d135d597728