title: High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis.
abstract: OBJECTIVE
  Adenocarcinoma, the most common non-small cell lung cancer is a leading cause of death worldwide, with a low overall survival (OS) despite increasing attempts to achieve an early diagnosis and accomplish surgical and multimodality treatment strategies. Cellular retinol binding protein-1 (CRBP-1) regulates retinol bioavailability and cell differentiation, but its role in lung cancerogenesis remains uncertain.
  
  
  METHODS
  CRBP-1 expression, clinical outcome and other prognostic factors were investigated in 167 lung adenocarcinoma patients. CRBP-1 expression was evaluated by immunohistochemistry of tissue microarray sections, gene copy number analysis and tumor methylation specific PCR. Effects of CRBP-1 expression on proliferation/apoptosis gene array, protein and transcripts were investigated in transfected A549 lung adenocarcinoma cells.
  
  
  RESULTS
  CRBP-1(High) expression was observed in 62.3% of adenocarcinomas and correlated with increased tumor grade and reduced OS as an independent prognostic factor. CRBP-1 gene copy gain also associated with tumor CRBP-1(High) status and dedifferentiation. CRBP-1-transfected (CRBP-1(+)) A549 grew more than CRBP-1(-) A549 cells. At >1μM concentrations, all trans-retinoic acid and retinol reduced viability more in CRBP-1(+) than in CRBP-1(-) A549 cells. CRBP-1(+) A549 cells showed up-regulated RARα/ RXRα and proliferative and transcriptional genes including pAkt, pEGFR, pErk1/2, creb1 and c-jun, whereas RARβ and p53 were strongly down-regulated; pAkt/pErk/ pEGFR inhibitors counteracted proliferative advantage and increased RARα/RXRα, c-jun and CD44 expression in CRBP-1(+) A549 cells.
  
  
  CONCLUSIONS
  CRBP-1(High) expression in lung adenocarcinoma correlated with increased tumor grade and reduced OS, likely through increased Akt/Erk/EGFR-mediated cell proliferation and differentiation. CRBP-1(High) expression can be considered an additional marker of poor prognosis in lung adenocarcinoma patients.
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Doldo
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Gaetana
authors.initials: G
authors.lastname: Costanza
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Ferlosio
authors.affiliation: Thoracic Surgery, Tor Vergata Policlinic of Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Pompeo
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Agostinelli
authors.affiliation: Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Bellezza
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Mazzaglia
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giunta
authors.affiliation: Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sidoni
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy; Department of Anatomic Pathology, Tor Vergata Policlinic of Rome, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
keywords: Akt; CRBP-1; EGFR; Erk; lung cancer; prognostic marker; survival