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Doldo E, Costanza G, Ferlosio A, et al. High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis. Genes Cancer. 2015;6(11):490-502doi: 10.18632/genesandcancer.89.
Doldo, E., Costanza, G., Ferlosio, A., Pompeo, E., Agostinelli, S., Bellezza, G., Mazzaglia, D., Giunta, A., Sidoni, A., & Orlandi, A. (2015). High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis. Genes & cancer, 6(11), 490-502. https://doi.org/10.18632/genesandcancer.89
Doldo, Elena, et al. "High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis." Genes & cancer vol. 6,11 (2015): 490-502. doi: https://doi.org/10.18632/genesandcancer.89
Doldo E, Costanza G, Ferlosio A, Pompeo E, Agostinelli S, Bellezza G, Mazzaglia D, Giunta A, Sidoni A, Orlandi A. High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis. Genes Cancer. 2015 Nov;6(11):490-502. doi: 10.18632/genesandcancer.89. PMID: 26807202; PMCID: PMC4701228.
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Genes Cancer. 2015 Nov;6(11):490-502. doi: 10.18632/genesandcancer.89.

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

Genes & cancer

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

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.

PMID: 26807202 PMCID: PMC4701228 DOI: 10.18632/genesandcancer.89

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

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