Published online before print May 8, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070981

Accepted for publication February 20, 2008.

Article

CUB-Domain-Containing Protein 1 Regulates Peritoneal Dissemination of Gastric Scirrhous Carcinoma

Takamasa Uekita^*, Masamitsu Tanaka^*, Misato Takigahira, Yuri Miyazawa^*, Yukihiro Nakanishi, Yae Kanai, Kazuyoshi Yanagihara, and Ryuichi Sakai^*@

From the Growth Factor* and Pathology Divisions and the Central Animal Laboratory, National Cancer Center Research Institute, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: rsakai{at}gan2.res.ncc.go.jp.

	Abstract

CUB-domain-containing protein 1 (CDCP1) is a type-I transmembrane protein that is highly expressed in colon, breast, and lung cancers. We recently revealed that CDCP1 is associated with and phosphorylated by Src family kinases and is involved in the regulation of anchorage independence of certain lung cancer cell lines. In this study, we examined whether CDCP1 is involved in the regulation of tumor progression of scirrhous gastric cancer, which is a diffusely infiltrative carcinoma with high invasion potential. Expression and phosphorylation levels of CDCP1 correlated with the invasive potential of scirrhous gastric cancers. Reduction of CDCP1 expression by siRNA suppressed migration, invasion, and anchorage independence without affecting the proliferation of highly invasive scirrhous gastric cancer cells. However, CDCP1 overexpression promoted gastric cancer cell migration with low potential of invasion. Loss of CDCP1 suppressed invasion and dissemination of cancer cells that were orthotopically implanted in the gastric wall of nude mice. Expression and phosphorylation of CDCP1 were also detected in cancer cells of surgically resected tissues of human scirrhous gastric cancer by immunohistochemical analysis. Our results suggest that CDCP1 promotes invasion and peritoneal dissemination of cancer cells through the regulation of cell migration and anchorage independence. Therefore, it is both a potential prognostic and therapeutic target in certain types of gastrointestinal cancers, and suppression of its phosphorylation might be a useful strategy for modulating cancer metastasis.