Oncotarget

Research Papers:

The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis

Guangchun Jin, Kosuke Sakitani, Hongshan Wang, Ying Jin, Alexander Dubeykovskiy, Daniel L. Worthley, Yagnesh Tailor and Timothy C. Wang _

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Oncotarget. 2017; 8:40606-40619. https://doi.org/10.18632/oncotarget.16506

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Abstract

Guangchun Jin1,2, Kosuke Sakitani1, Hongshan Wang1,3, Ying Jin1, Alexander Dubeykovskiy1, Daniel L. Worthley4, Yagnesh Tailor1 and Timothy C. Wang1

1Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA

2The Research Institute, Yanbian University Hospital, Jilin, China

3Department of General surgery, Zhongshan Hospital, Fudan University, Shanghai, China

4South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, South Australia, Australia

Correspondence to:

Timothy C. Wang, email: tcw21@columbia.edu

Keywords: GPR56, progastrin, proliferation, stem cell, colorectal cancer

Abbreviations: Human progastrin (hGAS), G-protein coupled receptor 56 (GPR56), 5-bromo-2’-deoxyuridine (BrdU), Bone morphogenetic protein (BMP).

Received: November 02, 2016    Accepted: February 22, 2017    Published: March 23, 2017

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.


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