Cheepala Satish B, Syed Zanobia, Trutschl Marjan, Cvek Urska, Clifford John L
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
Mol Carcinog. 2007 Aug;46(8):634-9. doi: 10.1002/mc.20346.
Despite the use of retinoids in the clinic for many years, their mode of action in the prevention of skin cancer is still unclear. Recent microarray analyses of the chemopreventive effect of all-trans retinoic acid (ATRA), one of the primary naturally occurring biologically active retinoids, in the two-stage mouse skin chemical carcinogenesis model have provided novel insight into their action. Comparison of the gene expression profiles of control skin to skin subjected to the two-stage protocol for 3 wk, with or without ATRA, has shown that approximately half of the genes regulated by 12-o-tetradecanoylphorbol-13-acetate (TPA) are oppositely regulated when ATRA is coadministered with TPA. It was further shown the Raf/Mek/Erk branch of mitogen-activated protein (MAP) kinase pathway contains a disproportionate number of oppositely regulated genes, thereby implicating it as one of the key pathways involved in tumor promotion by TPA, that is blocked by ATRA. This result has pointed the way toward the detailed study of Raf/Mek/Erk pathway signaling in skin cancer development and its potential as a target pathway for chemoprevention by ATRA and other chemopreventive drugs.
尽管维甲酸类药物已在临床上使用多年，但其预防皮肤癌的作用机制仍不清楚。近期，对全反式维甲酸（ATRA）（一种主要的天然生物活性维甲酸类药物）在两阶段小鼠皮肤化学致癌模型中的化学预防作用进行的微阵列分析，为其作用机制提供了新的见解。将对照皮肤与接受两阶段方案3周（有无ATRA）的皮肤的基因表达谱进行比较，结果表明，当ATRA与12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）共同给药时，约一半受TPA调控的基因呈现相反的调控。进一步研究表明，丝裂原活化蛋白（MAP）激酶途径的Raf/Mek/Erk分支包含数量不成比例的相反调控基因，这表明该途径是TPA促进肿瘤发生的关键途径之一，而ATRA可阻断该途径。这一结果为深入研究Raf/Mek/Erk途径信号在皮肤癌发生中的作用以及其作为ATRA和其他化学预防药物化学预防靶点途径的潜力指明了方向。
