title: Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma.
abstract: BACKGROUND
  The overexpression of receptor tyrosine kinase EphA2 has been reported in various cancers. In non-small cell lung cancer (NSCLC), a positive correlation has been reported between high EphA2 immunohistochemical staining level and poor prognosis. However, its ligand, ephrin-A1, is supposed to act as a tumor suppressor via the kinase activity of EphA2. Thus, the biphasic roles of this system are not fully elucidated. We retrospectively evaluated the expression levels of EphA2 and ephrin-A1 in surgically treated pathological (p-) stage I NSCLC tumor samples, and their relation to clinicopathologic features or postoperative prognoses.
  
  
  METHODS
  The levels of EphA2 and ephrin-A1 mRNA expression were quantified by real-time reverse-transcription polymerase chain reaction in tissue samples from p-stage I NSCLC patients who had undergone complete resection in our facility (n=195). They were divided into two (EphA2/ephrin-A1-Low and -High) groups based on the median expression level, and their respective clinicopathologic features and prognoses were analyzed. Furthermore, samples were stained immunohistochemically and classified into four groups according to their staining levels, and their prognoses analyzed.
  
  
  RESULTS
  Marked demographic differences were found between EphA2/ephrin-A1-Low and -High groups. Both EphA2-High and ephrin-A1-High groups had more females, no smoking history, adenocarcinoma histology, well-differentiated carcinomas, p-stage IA patients, and patients with EGFR gene mutations. Five-year overall survival rates of the EphA2-Low and the EphA2-High patient groups were 68.9% and 86.1%, respectively (P=0.017), and five-year disease-free survival rates were 69.9% and 83.2%, respectively (P=0.035). There were no statistical differences between ephrin-A1-Low and ephrin-A1-High groups concerning postoperative survival. Although showing smaller differences, the findings from the immunohistochemical analyses supported the above results.
  
  
  CONCLUSIONS
  Higher expression of EphA2 and ephrin-A1 was more related to the female sex, reduced smoking status, adenocarcinoma, well differentiated carcinomas, p-stage IA, and EGFR gene mutations. Higher EphA2 mRNA expression in p-stage I NSCLC patients was positively related to improved prognoses. These results may reflect a tumor suppressive role for the EphA2/ephrin-A1 system in a population of patients restricted to p-stage I NSCLC.
authors.affiliation: Faculty of Medicine, Department of Thoracic Surgery, Kyoto University, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Miyahara
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.forename: Marika
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Toshi
authors.initials: T
authors.lastname: Mennju
authors.forename: Ei
authors.initials: E
authors.lastname: Nakayama
authors.forename: Masashi
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Kikuchi
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitamura
authors.forename: Naoto
authors.initials: N
authors.lastname: Imamura
authors.forename: Cheng-Long
authors.initials: CL
authors.lastname: Huang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D036382:Ephrin-A1 / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011184:Postoperative Period; D012333:RNA, Messenger / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D036382:Ephrin-A1; D012333:RNA, Messenger; D036104:Receptor, EphA2