High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis
Elena Doldo1, Gaetana Costanza1, Amedeo Ferlosio1, Eugenio Pompeo2, Sara Agostinelli1, Guido Bellezza3, Donatella Mazzaglia1, Alessandro Giunta1, Angelo Sidoni3 and Augusto Orlandi1,4
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 Department of Anatomic Pathology, Tor Vergata Policlinic of Rome, Italy
Correspondence:
Augusto Orlandi, email:
Keywords: lung cancer, CRBP-1, Akt, Erk, EGFR, prognostic marker, survival
Received: August 13, 2015 Accepted: November 15, 2015 Published: November 19, 2015
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 investigatedin transfected A549 lung adenocarcinoma cells.
Results: CRBP-1High 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-1High 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-1High expression in lung adenocarcinoma correlated with increased tumor grade and reduced OS, likely through increased Akt/Erk/EGFR-mediated cell proliferation and differentiation. CRBP-1High expression can be considered an additional marker of poor prognosis in lung adenocarcinoma patients.
