The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis.
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.
['Jin|Guangchun|G|', 'Sakitani|Kosuke|K|', 'Wang|Hongshan|H|', 'Jin|Ying|Y|', 'Dubeykovskiy|Alexander|A|', 'Worthley|Daniel L|DL|', 'Tailor|Yagnesh|Y|', 'Wang|Timothy C|TC|']
D000818:Animals D017209:Apoptosis D063646:Carcinogenesis D045744:Cell Line, Tumor D049109:Cell Proliferation D003106:Colon D003110:Colonic Neoplasms D005755:Gastrins D006801:Humans D007413:Intestinal Mucosa D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008822:Mice, Transgenic D011485:Protein Binding D011498:Protein Precursors D043887:Receptor, Cholecystokinin B D043562:Receptors, G-Protein-Coupled D013234:Stem Cells
progastrin proliferation colorectal cancer GPR56 stem cell