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Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

¹ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Departments of ² Molecular and Internal Medicine, ³ Molecular Pathology, and ⁴ Pathology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; ⁵ Department of Thoracic Surgery, Saitama Cancer Center, Saitama, Japan; and ⁶ Division of Thoracic Surgery and ⁷ Molecular Pathology and Genetics Division, Kanagawa Cancer Center, Kanagawa, Japan

Requests for reprints: Yataro Daigo, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 Japan. Phone: 81-3-5449-5457; Fax: 81-3-5449-5406; E-mail: ydaigo{at}ims.u-tokyo.ac.jp

Key Words: Nectin-4 • therapeutic target • biomarker • lung cancer

Gene expression profile analysis of lung cancers revealed the transactivation of an immunoglobulin-like molecule Nectin-4 in the majority of non–small cell lung cancers (NSCLC). Immunohistochemical staining of 422 NSCLCs showed that a high level of Nectin-4 expression was associated with poor prognosis for NSCLC patients (P < 0.0001), and multivariate analysis confirmed its independent prognostic value (P < 0.0001). We established an ELISA to measure serum Nectin-4 and found that serum Nectin-4 levels were significantly higher in NSCLC patients than in healthy volunteers. The proportion of the serum Nectin-4–positive cases was 88 of 164 (53.7%) NSCLCs, whereas only 3 of 131 (2.3%) healthy volunteers were falsely diagnosed as positive, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA21-1) in sensitivity and specificity. A combined ELISA for both Nectin-4 and CEA increased sensitivity and classified 65.0% of lung adenocarcinomas as positive with false-positive rate of 4.6%. The use of both Nectin-4 and CYFRA21-1 classified 68.3% of lung squamous cell carcinomas as positive with false-positive rate of 6.1%. Treatment of lung cancer cells with small interfering RNAs against Nectin-4 suppressed its expression and cell growth. In addition, exogenous expression of Nectin-4 increased the lamellipodia formation and the invasive ability of mammalian cells through activation of small GTPase Rac1. Nectin-4 might play a significant role in lung carcinogenesis, and it should be a new candidate serum and tissue biomarker, as well as a therapeutic target. [Cancer Res 2009;69(16):6694–703]

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