title: Loss of CRABP-II Characterizes Human Skin Poorly Differentiated Squamous Cell Carcinomas and Favors DMBA/TPA-Induced Carcinogenesis.
abstract: Retinol and its derivatives play an important role in epidermal growth and differentiation and represent chemopreventive agents in nonmelanoma skin cancer. Retinoic acid binding protein II (CRABP-II) is a cytoplasmic receptor that critically regulates all-trans-retinoic acid (ATRA) trafficking. We documented the marked reduced expression of CRABP-II and its promoter methylation in human poorly differentiated squamous cell carcinomas. To investigate the role of CRABP-II in skin carcinogenesis we used skin lesion induction by dimethylbenz[a]anthracene/12-O-tetradecanoyl-phorbol-13-acetate in CRABP-II-knockout C57BL/6 mice. We observed earlier and more diffuse epidermal dysplasia, greater incidence and severity of tumors, reduced expression of cytokeratin 1/cytokeratin 10 and involucrin, increased proliferation, and impaired ATRA inhibition of tumor promotion compared with wild-type animals. CRABP-II-transfected HaCaT, FaDu, and A431 cells showed expression of differentiation markers, retinoic acid receptor-β/-γ signaling, ATRA sensitivity, and suppression of EGFR/v-akt murine thymoma viral oncogene homolog 1 (AKT) pathways in a fatty acid binding protein 5/peroxisome proliferator-activated receptor-β/-δ-independent manner. The opposite was true in keratinocytes isolated from CRABP-II-knockout mice. Finally, CRABP-II accumulation induced ubiquitination-associated reduction of EGFR. Our results showed reduced CRABP-II expression in human poorly differentiated squamous cell carcinomas, and its gene deletion favored experimental skin carcinogenesis and impaired ATRA antitumor efficacy, likely modulating EGFR/AKT pathways and retinoic acid receptor-β/-γ signaling. Therapeutic interventions aimed at restoring CRABP-II-mediated signaling may amplify therapeutic retinoid efficacy in nonmelanoma skin cancer.
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
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: Chiara
authors.initials: C
authors.lastname: Tarquini
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: Donatella
authors.initials: D
authors.lastname: Mazzaglia
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: Dermatology, Department of Internal Medicine, Tor Vergata University of Rome, Italy; Policlinic of Tor Vergata University of Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Campione
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Di Stefani
authors.affiliation: Dermatology, Department of Internal Medicine, Tor Vergata University of Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giunta
authors.affiliation: Dermatology, Department of Internal Medicine, Tor Vergata University of Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bianchi
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy; Policlinic of Tor Vergata University of Rome, Italy. Electronic address: orlandi@uniroma2.it.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism; D000818:Animals; D001707:Biopsy, Needle; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D019175:DNA Methylation; D004195:Disease Models, Animal; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D019396:Tissue Polypeptide Antigen / Q000378:metabolism; D014162:Transfection
chemical_list: D018168:Receptors, Retinoic Acid; D019396:Tissue Polypeptide Antigen; C082928:retinoic acid binding protein II, cellular; D015127:9,10-Dimethyl-1,2-benzanthracene; C541485:EGFR protein, mouse; D066246:ErbB Receptors