title: EphA2 in the early pathogenesis and progression of non-small cell lung cancer.
abstract: Overexpression of the receptor tyrosine kinase EphA2 occurs in non-small cell lung cancer (NSCLC) and a number of other human cancers. This overexpression correlates with a poor prognosis, smoking, and the presence of Kirsten rat sarcoma (K-Ras) mutations in NSCLC. In other cancers, EphA2 has been implicated in migration and metastasis. To determine if EphA2 can promote NSCLC progression, we examined the relationship of EphA2 with proliferation and migration in cell lines and with metastases in patient tumors. We also examined potential mechanisms involving AKT, Src, focal adhesion kinase, Rho guanosine triphosphatases (GTPase), and extracellular signal-regulated kinase (ERK)-1/2. Knockdown of EphA2 in NSCLC cell lines decreased proliferation (colony size) by 20% to 70% in four of five cell lines (P < 0. 04) and cell migration by 7% to 75% in five of six cell lines (P < 0. 03). ERK1/2 activation correlated with effects on proliferation, and inhibition of ERK1/2 activation also suppressed proliferation. In accordance with the in vitro data, high tumor expression of EphA2 was an independent prognostic factor in time to recurrence (P = 0.057) and time to metastases (P = 0.046) of NSCLC patients. We also examined EphA2 expression in the putative premalignant lung lesion, atypical adenomatous hyperplasia, and the noninvasive bronchioloalveolar component of adenocarcinoma because K-Ras mutations occur in atypical adenomatous hyperplasia and are common in lung adenocarcinomas. Both preinvasive lesion types expressed EphA2, showing its expression in the early pathogenesis of lung adenocarcinoma. Our data suggest that EphA2 may be a promising target for treating and preventing NSCLC.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Brannan
authors.forename: Banibrata
authors.initials: B
authors.lastname: Sen
authors.forename: Babita
authors.initials: B
authors.lastname: Saigal
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Luisa
authors.initials: L
authors.lastname: Solis
authors.forename: Wenli
authors.initials: W
authors.lastname: Dong
authors.forename: B Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D036104:Receptor, EphA2 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D012333:RNA, Messenger; D066246:ErbB Receptors; D036104:Receptor, EphA2; D048049:Extracellular Signal-Regulated MAP Kinases