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GUCY2C hormone deficiency contributes to diet‐induced colorectal tumorigenesis
Author(s) -
Lin Jieru Egeria,
ColonGonzalez Francheska,
Kim Gilbert Won,
Li Peng,
Blomain Erik Scott,
Marszalowicz Glen,
Stoecker Brian Arthur,
Waldman Scott Arthur
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1104.8
Subject(s) - carcinogenesis , colorectal cancer , gene silencing , endocrinology , cancer research , medicine , azoxymethane , cancer , hormone , paracrine signalling , biology , receptor , genetics , gene
While diet and obesity increase the risk for colorectal cancer (CRC), mechanisms underlying this association remain undefined. Guanylyl cyclase C (GUCY2C) is the intestinal receptor for the paracrine hormone guanylin. GUCY2C silencing, reflecting loss of guanylin expression, universally contributes to colorectal cancer initiation and progression. Indeed, silencing the GUCY2C tumor suppressor accelerates the cell cycle, increases DNA damage, and reprograms cell metabolism, increasing genetic and carcinogen‐induced colorectal cancer. Here, we reveal that excess calorie ingestion underlying obesity recapitulates mechanisms underlying CRC by eliminating guanylin expression, silencing the GUCY2C tumor suppressor, promoting intestinal tumorigenesis. Suppression of guanylin is reversibly modulated by ingested calories, rather than by the endocrine, adipokine or inflammatory milieu of obesity. Moreover, transgenic expression of guanylin, which is resistant to diet‐induced suppression, prevented colorectal cancer induced by excess calories in mice. Recent FDA approval of an oral GUYC2C ligand highlights the translational opportunities for GUCY2C hormone supplementation in preventing CRC in obesity.