Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion.
The Eph family of receptors is the largest family of receptor tyrosine kinases, but it remains poorly studied in lung cancer. We aimed to systematically explore the human Eph receptors and their ligands, the ephrins, in lung adenocarcinoma. The prognostic impact of Eph receptor and ephrin gene expression was analyzed using 2 independent cohorts of lung adenocarcinoma. Gene expression profiles in lung adenocarcinoma compared with normal adjacent lung were studied in 3 independent cohorts and in cell lines. Gene expression profiles were validated with quantitative polymerase chain reaction (qPCR) and Western blotting in cell lines. Functional studies to assess the role of Eph receptor A4 (EphA4) were carried out in vitro. The biological effects of EphA4 in lung cancer cell lines were assayed following overexpression and knockdown. Of the 11 Eph receptors and 8 ephrins analyzed, only EphA4 and ephrin A1 gene expression were consistently associated with an improved outcome in patients with lung adenocarcinoma. Expression levels of EphA4 by microarray correlated well with expression levels measured by qPCR and Western blotting. EphA4 overexpression reduced cell migration and invasion but did not affect cell cycle, apoptosis, or drug sensitivity. Surprisingly, EphA4 was expressed at higher levels in cancer compared with non-cancer tissues and cell lines. EphA4 gene expression is associated with an improved outcome in patients with resected lung adenocarcinoma, possibly by affecting cancer cell migration and invasion.
Department of 1Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center;5The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. psaintig@mdanderson.org
Pierre
P
Saintigny
Shaohua
S
Peng
Li
L
Zhang
Banibrata
B
Sen
Ignacio I
II
Wistuba
Scott M
SM
Lippman
Luc
L
Girard
John D
JD
Minna
John V
JV
Heymach
Faye M
FM
Johnson
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D018572:Disease-Free Survival; D036342:Ephrins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015999:Multivariate Analysis; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness; D062793:Occludin / Q000378:metabolism; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000494:pharmacology; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D036342:Ephrins; C568985:OCLN protein, human; D062793:Occludin; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D036122:Receptor, EphA4; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin