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Guanylyl Cyclase C is a Novel Tumor Susceptibility Gene in Colorectal Cancer. The most commonly lost gene products in colorectal carcinogenesis include guanylin and uroguanylin, the endogenous ligands for guanylyl cyclase C (GCC, GUCY2C), the intestinal receptor for diarrheagenic bacterial enterotoxins. The significance of loss of GCC ligands early in intestinal tumorigenesis remains obscure because (patho)physiological roles of GCC signaling in intestine, beyond regulation of intestinal fluid and electrolyte homeostasis, are poorly defined. Recently, signaling by GCC and its downstream effector, cyclic GMP (cGMP) has emerged as a principal regulator of proliferation in human colon cancer cells. In that context, differentiated enterocytes in villi exhibit higher guanylin expression and ligand-dependent cGMP accumulation compared to proliferating progenitor cells in crypts. These observations suggest that GCC signaling may regulate the renewal of the intestinal epithelium by restricting the proliferating compartment and promoting the transition from proliferation to differentiation along the crypt to villus axis. Here, the role of GCC in regulating normal enterocyte dynamics along the crypt-villus axis and the corruption of those mechanisms in tumorigenesis were explored. Elimination of GCC expression in mice (GCC-/-) increased crypt length along a decreasing rostral-caudal gradient by disrupting component homeostatic processes. Crypt expansion reflected hyperplasia of the proliferating compartment with reciprocal increases in rapidly cycling progenitor cells and reductions in differentiated cells of the secretory lineage, including Paneth and goblet, but not enteroendocrine, cells. In close agreement, induction of GCC signaling in mucosal sheets ex vivo and intestinal cells in vitro inhibited proliferation by activating cGMP-dependent protein kinase and delaying the cell cycle at the G1/S transition. Crypt hyperplasia in GCC-/- mice was associated with compensatory increases in cell migration and apoptosis. This novel role in restricting the proliferating compartment and organizing the crypt-villus axis suggests that dysregulation of GCC, reflecting loss of endogenous ligands, might contribute to tumorigenesis by potentiating hyperproliferation which, in turn, may amplify disruption of genomic integrity. Indeed, in colons of mice carrying mutations in Apc (ApcMin/+) or exposed to the carcinogen azoxymethane, elimination of GCC increased tumor initiation by corrupting genomic integrity in the context of disabled compensatory apoptosis. Separately, deletion of GCC increased tumor growth by releasing a restriction on the cell cycle normally constraining epithelial cell proliferation. This previously unrecognized role of GCC as a tumor suppressor by restricting proliferation and maintaining genomic integrity suggests that receptor dysregulation reflecting ligand insufficiency is a key event during early colorectal tumorigenesis. Together with the uniform over-expression of GCC in human tumors, and the standard of care in which hormone deficiencies are treated by replacement therapy, the role of GCC as a tumor suppressor underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer.
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Papers共 593 篇Author StatisticsCo-AuthorSimilar Experts
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crossref(2023)
crossref(2023)
Michael S. Magee,Tara S. Abraham,Trevor R. Baybutt,John C. Flickinger, Natalie A. Ridge,Glen P. Marszalowicz, Priyanka Prajapati,Adam R. Hersperger,Scott A. Waldman,Adam E. Snook
crossref(2023)
Michael S. Magee, Tara S. Abraham,Trevor R. Baybutt,John C. Flickinger, Natalie A. Ridge,Glen P. Marszalowicz, Priyanka Prajapati,Adam R. Hersperger,Scott A. Waldman,Adam E. Snook
crossref(2023)
crossref(2023)
JOURNAL OF NEUROCHEMISTRYno. 6 (2023): 719-732
crossref(2023)
The journal of investigative dermatology/Journal of investigative dermatologyno. 5 (2023): S183-S183
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#Papers: 589
#Citation: 20198
H-Index: 71
G-Index: 124
Sociability: 8
Diversity: 4
Activity: 39
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