Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer.

Abstract

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.

• Authors: Atsushi Takano, Nobuhisa Ishikawa, Ryohei Nishino, Ken Masuda, Wataru Yasui, Kouki Inai, Hitoshi Nishimura, Hiroyuki Ito, Haruhiko Nakayama, Yohei Miyagi, Eiju Tsuchiya, Nobuoki Kohno, Yusuke Nakamura, Yataro Daigo
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 16 Pg. 6694-703 (Aug 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19679554 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Cell Adhesion Molecules
• Oncogene Proteins
• RNA, Small Interfering
• NECTIN4 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor (blood)
• COS Cells
• Carcinoma, Non-Small-Cell Lung (blood, diagnosis, drug therapy, genetics)
• Cell Adhesion Molecules (antagonists & inhibitors, blood, genetics, physiology)
• Chlorocebus aethiops
• Drug Delivery Systems
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (blood, diagnosis, drug therapy, genetics)
• Male
• Mice
• Middle Aged
• NIH 3T3 Cells
• Oncogene Proteins (antagonists & inhibitors, blood, genetics, physiology)
• RNA, Small Interfering (pharmacology, therapeutic use)
• Tumor Cells, Cultured