Passeri Daniela, Doldo Elena, Tarquini Chiara, Costanza Gaetana, Mazzaglia Donatella, Agostinelli Sara, Campione Elena, Di Stefani Alessandro, Giunta Alessandro, Bianchi Luca, Orlandi Augusto
Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
Dermatology, Department of Internal Medicine, Tor Vergata University of Rome, Italy; Policlinic of Tor Vergata University of Rome, Italy.
J Invest Dermatol. 2016 Jun;136(6):1255-1266. doi: 10.1016/j.jid.2016.01.039. Epub 2016 Mar 2.
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.
视黄醇及其衍生物在表皮生长和分化中起重要作用，是非黑素瘤皮肤癌的化学预防剂。维甲酸结合蛋白II（CRABP-II）是一种细胞质受体，对全反式维甲酸（ATRA）的转运起关键调节作用。我们记录了CRABP-II在人低分化鳞状细胞癌中的表达显著降低及其启动子甲基化情况。为了研究CRABP-II在皮肤癌发生中的作用，我们在CRABP-II基因敲除的C57BL/6小鼠中使用二甲基苯并[a]蒽/12-O-十四烷酰佛波醇-13-乙酸酯诱导皮肤病变。与野生型动物相比，我们观察到更早且更弥漫的表皮发育异常、更高的肿瘤发生率和严重程度、细胞角蛋白1/细胞角蛋白10和内披蛋白的表达降低、增殖增加以及ATRA对肿瘤促进的抑制作用受损。CRABP-II转染的HaCaT、FaDu和A431细胞以脂肪酸结合蛋白5/过氧化物酶体增殖物激活受体-β/-δ非依赖性方式显示分化标志物的表达、视黄酸受体-β/-γ信号传导、ATRA敏感性以及表皮生长因子受体/v-akt小鼠胸腺瘤病毒癌基因同源物1（AKT）途径的抑制。从CRABP-II基因敲除小鼠分离的角质形成细胞中情况则相反。最后，CRABP-II的积累诱导了与泛素化相关的表皮生长因子受体减少。我们的结果表明CRABP-II在人低分化鳞状细胞癌中的表达降低，其基因缺失有利于实验性皮肤癌发生并损害ATRA的抗肿瘤功效，可能是通过调节表皮生长因子受体/AKT途径和视黄酸受体-β/-γ信号传导。旨在恢复CRABP-II介导信号传导的治疗干预可能会增强非黑素瘤皮肤癌中类维生素A的治疗效果。
