Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice.
Hyperproliferation of the colonic epithelium, leading to expansion of colonic crypt progenitors, is a recognized risk factor for colorectal cancer. Overexpression of progastrin, a nonamidated and incompletely processed product of the gastrin gene, has been shown to induce colonic hyperproliferation and promote colorectal cancer in mice, but the mechanism of pathogenesis has not been defined. Cholecystokinin-2 receptor (CCK2R) is the primary receptor for cholecystokinin (CCK) and amidated gastrin. Here, we show that Cck2r was expressed in murine colonic crypts and upregulated in the transgenic mice that overexpress human progastrin. Murine deletion of Cck2r abrogated progastrin-dependent increases in colonic proliferation, mucosal thickness, and beta-catenin and CD44 expression in the colon tumor. In addition, either deletion or antagonism of Cck2r resulted in the inhibition of progastrin-dependent increases in progenitors expressing doublecortin and CaM kinase-like-1 (DCAMKL1), stem cells expressing leucine rich repeat-containing G protein-coupled receptor 5 (LgR5), and colonic crypt fission. Furthermore, in the azoxymethane mouse model of colorectal carcinogenesis, Cck2r deletion in human progastrin-overexpressing mice resulted in markedly decreased aberrant crypt foci formation and substantially reduced tumor size and multiplicity. Taken together, these observations indicate that progastrin induces proliferative effects, primarily in colonic progenitor cells, through a CCK2R-dependent pathway. Moreover, our data suggest that CCK2R may be a potential target in the treatment or prevention of colorectal cancer.
Jin
Guangchun
G
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
Ramanathan
Vigneshwaran
V
Quante
Michael
M
Baik
Gwang Ho
GH
Yang
Xiangdong
X
Wang
Sophie S W
SS
Tu
Shuiping
S
Gordon
Shanisha A K
SA
Pritchard
David Mark
DM
Varro
Andrea
A
Shulkes
Arthur
A
Wang
Timothy C
TC
D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane / Q000633:toxicity; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005755:Gastrins / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
C476399:Cd44 protein, mouse; D005755:Gastrins; D018960:Hyaluronan Receptors; D011498:Protein Precursors; D043887:Receptor, Cholecystokinin B; D011994:Recombinant Proteins; C013706:big gastrin; D001397:Azoxymethane