Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for 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.
Takano
Atsushi
A
Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
Ishikawa
Nobuhisa
N
Nishino
Ryohei
R
Masuda
Ken
K
Yasui
Wataru
W
Inai
Kouki
K
Nishimura
Hitoshi
H
Ito
Hiroyuki
H
Nakayama
Haruhiko
H
Miyagi
Yohei
Y
Tsuchiya
Eiju
E
Kohno
Nobuoki
N
Nakamura
Yusuke
Y
Daigo
Yataro
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D019556:COS Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D002522:Chlorocebus aethiops; D016503:Drug Delivery Systems; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D000075983:Nectins
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C442228:NECTIN4 protein, human; D000075983:Nectins