High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis

Elena Doldo; Gaetana Costanza; Amedeo Ferlosio; Eugenio Pompeo; Sara Agostinelli; Guido Bellezza; Donatella Mazzaglia; Alessandro Giunta; Angelo Sidoni; Augusto Orlandi

doi:10.18632/genesandcancer.89

High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis

Genes Cancer. 2015 Nov;6(11-12):490-502. doi: 10.18632/genesandcancer.89.

Affiliations

¹ Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
² Thoracic Surgery, Tor Vergata Policlinic of Rome, Italy.
³ Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Italy.
⁴ Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy; Department of Anatomic Pathology, Tor Vergata Policlinic of Rome, Italy.

Abstract

Purpose: 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.

Experimental design: 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.

Conclusion: 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.

Keywords: Akt; CRBP-1; EGFR; Erk; lung cancer; prognostic marker; survival.