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Sci Rep. 2016 Mar 3;6:22371. doi: 10.1038/srep22371.

Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination.

Author information

1
Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
2
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
3
Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasyo, Uji, Kyoto 611-0011, Japan.
4
Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
5
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, College Road, Singapore 169857, Singapore.
6
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
7
Department of Surgery I, Oita University Faculty of Medicine, 1-1 Idaigaoka, Yufu, Oita 879-5593, Japan.
8
Gastric Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
9
Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya 663-8501, Japan.
10
Department of Translational Oncology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
11
Omori Red Cross Hospital, 4-30-11 Chuo, Ohta-ku, Tokyo 143-8527, Japan.
12
Division of Translational Research, Exploratory Oncology Research &Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan.

Abstract

Peritoneal dissemination is the most frequent, incurable metastasis occurring in patients with advanced gastric cancer (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to provide novel insights into the molecular mechanisms that drive the peritoneal dissemination of GC. We performed combined expression analysis with in vivo-selected metastatic cell lines and samples from 200 GC patients to identify driver genes of peritoneal dissemination. The driver-gene functions associated with GC dissemination were examined using a mouse xenograft model. We identified a peritoneal dissemination-associated expression signature, whose profile correlated with those of genes related to development, focal adhesion, and the extracellular matrix. Among the genes comprising the expression signature, we identified that discoidin-domain receptor 2 (DDR2) as a potential regulator of peritoneal dissemination. The DDR2 was upregulated by the loss of DNA methylation and that DDR2 knockdown reduced peritoneal metastasis in a xenograft model. Dasatinib, an inhibitor of the DDR2 signaling pathway, effectively suppressed peritoneal dissemination. DDR2 was identified as a driver gene for GC dissemination from the combined expression signature and can potentially serve as a novel therapeutic target for inhibiting GC peritoneal dissemination.

PMID:
26934957
PMCID:
PMC4776110
DOI:
10.1038/srep22371
[Indexed for MEDLINE]
Free PMC Article

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