Journal article

Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

Trevelyan R Menheniott, Louise O'Connor, Yok Teng Chionh, Jan Daebritz, Michelle Scurr, Benjamin N Rollo, Garrett Z Ng, Shelley Jacobs, Angelique Catubig, Bayzar Kurklu, Stephen Mercer, Toshinari Minamoto, David E Ong, Richard L Ferrero, James G Fox, Timothy C Wang, Philip Sutton, Louise M Judd, Andrew S Giraud

JOURNAL OF CLINICAL INVESTIGATION | AMER SOC CLINICAL INVESTIGATION INC | Published : 2016

Abstract

Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhi..

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Grants

Awarded by National Health and Medical Research Council (NHMRC)


Awarded by German Research Foundation


Awarded by NATIONAL CANCER INSTITUTE


Awarded by Grants-in-Aid for Scientific Research


Funding Acknowledgements

We thank the Australian Phenomics Network for assistance with generation of Gkn2<SUP>-/-</SUP> mice and Elizabeth Williams for pronuclear injections of BAC DNA and generation of transgenic mice at the Transgenic Animal Service of Queensland, University of Queensland, St. Lucia, Australia. We thank Matthew Burton, the Flow Cytometry and Imaging Facility, Murdoch Children's Research Institute, for advice and assistance with flow cytometry analysis. This study was supported by a project grant (1047208) from the National Health and Medical Research Council (NHMRC); research fellowships awarded to T.R. Menheniott (1026674), A.S. Giraud (607330), L.M. Judd (1008776) and P. Sutton (1020387) by the NHMRC; a fellowship (DFG DA1161/5-1) awarded to J. Dabritz by the German Research Foundation; and the Victorian Government's Medical Research Operational Infrastructure Support Program.