title: Expression of the GLI family genes is associated with tumor progression in advanced lung adenocarcinoma.
abstract: BACKGROUND
  The hedgehog (Hh) signaling pathway is aberrantly activated in various cancers. Expression of the GLI family of genes, which encode for transcriptional factors of the Hh pathway, has not been fully assessed in clinical samples of advanced lung adenocarcinoma. In this study, we retrospectively evaluated the expression of the GLI family of genes in advanced stage lung adenocarcinoma samples and determined their relation to patient survival.
  
  
  METHODS
  The levels of GLI1, GLI2, and GLI3 mRNA expression were measured by quantitative real-time polymerase chain reaction in surgically obtained tissue samples from stage II-IV lung adenocarcinoma patients (n = 102). Pairwise comparisons between all three GLI mRNA expression were performed, and after dichotomizing the patients into low and high expression groups according to each GLI mRNA expression level, survival curves were calculated and multivariate analyses were conducted.
  
  
  RESULTS
  Significant positive correlation was found between GLI1 and GLI3 mRNA expression (P <0.001). Tumors with higher expression (upper 15%) of GLI1 or GLI3 mRNA were associated with poor survival in stage II-IV (5-year overall survival rates: GLI1 mRNA low, 41.7% vs. high, 20.0%, P = 0.0074; GLI3 mRNA low, 43.1% vs. high, 13.3%, P = 0.0062) and stage III-IV (5-year overall survival rates: GLI1 mRNA low, 34.0% vs. high, 0%, P = 0.0012; GLI3 mRNA low, 33.4% vs. high, 7.7%, P = 0.057) lung adenocarcinoma patients. GLI2 mRNA expression did not appear to have great clinical significance. Multivariate analysis revealed higher GLI1 mRNA expression as an independent factor for unfavorable patient survival (P = 0.0030, hazard ratio = 3.1, 95% confidence interval = 1.5-6.2), as well as tumor differentiation and stage.
  
  
  CONCLUSIONS
  Expression of GLI1 and GLI3 mRNA was strongly correlated, and their overexpression, especially that of GLI1, was found to be predictive of aggressive tumor behavior. This study indicates that the Hh pathway may be a key oncogenic signaling network in tumor pathogenesis and, thus, a potential therapeutic target in advanced lung adenocarcinoma.
authors.affiliation: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. mishi@kuhp.kyoto-u.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.forename: Naoto
authors.initials: N
authors.lastname: Imamura
authors.forename: Terumasa
authors.initials: T
authors.lastname: Sowa
authors.forename: Kei
authors.initials: K
authors.lastname: Shikuma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: D014408:Biomarkers, Tumor; C400551:GLI1 protein, human; C082593:GLI2 protein, human; C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
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