Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity.
OBJECTIVE
The most commonly lost gene products in colorectal carcinogenesis include guanylin and uroguanylin, endogenous ligands for guanylyl cyclase C (GCC). Beyond intestinal fluid balance, GCC mediates diarrhea induced by bacterial enterotoxins, and an inverse relationship exists between enterotoxigenic Escherichia coli infections producing the exogenous GCC ligand ST and colorectal cancer worldwide. However, the role of GCC in neoplasia remains obscure.


METHODS
Intestinal tumorigenesis was examined in wild-type (Gcc(+/+)) and GCC-deficient (Gcc(-/-)) mice carrying mutations in Apc (Apc(Min/+)) or exposed to the carcinogen azoxymethane. Markers of DNA damage, loss of Apc heterozygosity, and beta-catenin mutations were used to assess genomic integrity. Hyperproliferation was explored using Ki67 and cell cycle markers. Apoptosis was quantified by transferase biotin-dUTP nick end labeling analysis.


RESULTS
In colons of Apc(Min/+) mice, deletion of Gcc increased tumor incidence and multiplicity, reflecting uncoupling of loss of genomic integrity and compensatory apoptosis. Conversely, in the small intestine, elimination of Gcc increased tumorigenesis by enhancing proliferation without altering genomic integrity. Moreover, these distinct but mutually reinforcing mechanisms collaborate in azoxymethane-exposed mice, and deletion of Gcc increased tumor initiation and growth associated with hypermutation and hyperproliferation, respectively, in conjunction with attenuated apoptosis.


CONCLUSIONS
GCC suppresses tumor initiation and growth by maintaining genomic integrity and restricting proliferation. This previously unrecognized role of GCC in inhibiting tumorigenesis, together with the invariant disruption in guanylin and uroguanylin expression early in carcinogenesis, and the uniform over-expression of GCC by tumors, underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer.
Department of Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Peng
P
Li
Stephanie
S
Schulz
Alessandro
A
Bombonati
Juan P
JP
Palazzo
Terry M
TM
Hyslop
Yihuan
Y
Xu
Amy A
AA
Baran
Linda D
LD
Siracusa
Giovanni M
GM
Pitari
Scott A
SA
Waldman
D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane; D018797:Cell Cycle Proteins / Q000032:analysis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004249:DNA Damage; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006162:Guanylate Cyclase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007421:Intestine, Small / Q000201:enzymology* / Q000473:pathology; D019394:Ki-67 Antigen / Q000032:analysis; D019656:Loss of Heterozygosity; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D018000:Receptors, Peptide; D051176:beta Catenin; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D001397:Azoxymethane