title: The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis.
abstract: Overexpression of human progastrin increases colonic mucosal proliferation and colorectal cancer progression in mice. The G-protein coupled receptor 56 (GPR56) is known to regulate cell adhesion, migration, proliferation and stem cell biology, but its expression in the gut has not been studied. We hypothesized that the promotion of colorectal cancer by progastrin may be mediated in part through GPR56. Here, we found that GPR56 expresses in rare colonic crypt cells that lineage trace colonic glands consistent with GPR56 marking long-lived colonic stem-progenitor cells. GPR56 was upregulated in transgenic mice overexpressing human progastrin. While recombinant human progastrin promoted the growth and survival of wild-type colonic organoids in vitro, colonic organoids cultured from GPR56-/- mice were resistant to progastrin. We found that progastrin directly bound to, and increased the proliferation of, GPR56-expressing colon cancer cells in vitro, and proliferation was increased in cells that expressed both GPR56 and the cholecystokinin-2 receptor (CCK2R). In vivo, deletion of GPR56 in the mouse germline abrogated progastrin-dependent colonic mucosal proliferation and increased apoptosis. Loss of GPR56 also inhibited progastrin-dependent colonic crypt fission and colorectal carcinogenesis in the azoxymethane (AOM) mouse model of colorectal cancer. Overall, we found that progastrin binds to GPR56 expressing colonic stem cells, which in turn promotes their expansion, and that this GPR56-dependent pathway is an important driver and potential new target in colorectal carcinogenesis.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.|The Research Institute, Yanbian University Hospital, Jilin, China.
authors.forename: Guangchun
authors.initials: G
authors.lastname: Jin
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sakitani
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.|Department of General surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dubeykovskiy
authors.affiliation: South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Tailor
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005755:Gastrins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D043887:Receptor, Cholecystokinin B / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D005755:Gastrins; D011498:Protein Precursors; D043887:Receptor, Cholecystokinin B; D043562:Receptors, G-Protein-Coupled; C524781:Adgrg1 protein, mouse; C013706:big gastrin
keywords: GPR56; colorectal cancer; progastrin; proliferation; stem cell