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.
Passeri, D., Doldo, E., Tarquini, C., Costanza, G., Mazzaglia, D., Agostinelli, S., et al. (2016). Loss of CRABP-II Characterizes Human Skin Poorly Differentiated Squamous Cell Carcinomas and Favors DMBA/TPA-Induced Carcinogenesis. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 136(6), 1255-1266.
|Tipologia:||Articolo su rivista|
|Citazione:||Passeri, D., Doldo, E., Tarquini, C., Costanza, G., Mazzaglia, D., Agostinelli, S., et al. (2016). Loss of CRABP-II Characterizes Human Skin Poorly Differentiated Squamous Cell Carcinomas and Favors DMBA/TPA-Induced Carcinogenesis. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 136(6), 1255-1266.|
|Settore Scientifico Disciplinare:||Settore MED/35 - Malattie Cutanee e Veneree|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jid.2016.01.039|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2016|
|Titolo:||Loss of CRABP-II Characterizes Human Skin Poorly Differentiated Squamous Cell Carcinomas and Favors DMBA/TPA-Induced Carcinogenesis|
|Autori:||Passeri, D; Doldo, E; Tarquini, C; Costanza, G; Mazzaglia, D; Agostinelli, S; Campione, E; Di Stefani, A; Giunta, A; Bianchi, L; Orlandi, A|
|Appare nelle tipologie:||01 - Articolo su rivista|