Meeran Syed M, Mantena Sudheer K, Elmets Craig A, Katiyar Santosh K
Department of Dermatology, University of Alabama at Birmingham and Birmingham VA Medical Center, Birmingham, Alabama 35294, USA.
Cancer Res. 2006 May 15;66(10):5512-20. doi: 10.1158/0008-5472.CAN-06-0218.
We have shown previously that topical application of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, prevents photocarcinogenesis in mice. EGCG prevents UVB-induced immunosuppression by inducing interleukin-12 (IL-12). As immunosuppression is a risk factor for photocarcinogenesis, we investigated the possibility that EGCG also prevents UVB-induced photocarcinogenesis through an IL-12-dependent DNA repair mechanism. To investigate this possibility, we determined the effects of EGCG on photocarcinogenesis in IL-12 knockout (KO) mice using the formation of cyclobutane pyrimidine dimers (CPD) as an indicator of the extent of UVB-induced DNA damage. Topical application of EGCG (1 mg/cm(2) skin) prevented photocarcinogenesis in wild-type (C3H/HeN) mice in terms of tumor incidence and tumor multiplicity but did not prevent photocarcinogenesis in IL-12 KO mice. UVB-induced DNA damage, as determined by the formation of CPDs and the number of sunburn cells, was resolved more rapidly in the skin of wild-type mice treated with EGCG than untreated control mice. In contrast, the extent of UVB-induced DNA damage and the numbers of sunburn cells were not significantly different in the EGCG-treated IL-12 KO mice and untreated control mice. In addition, treatment of XPA-proficient human fibroblast cells with EGCG promoted repair of UVB-induced CPDs in a dose-dependent manner but not in an XPA-deficient cells, indicating that the nucleotide excision repair mechanism is involved in EGCG-mediated DNA repair. Taken together, these results indicate for the first time that EGCG can prevent photocarcinogenesis through an EGCG-induced IL-12-dependent DNA repair mechanism.
我们之前已经表明，局部应用绿茶中的主要多酚（-）-表没食子儿茶素-3-没食子酸酯（EGCG）可预防小鼠光致癌作用。EGCG通过诱导白细胞介素-12（IL-12）来预防紫外线B（UVB）诱导的免疫抑制。由于免疫抑制是光致癌作用的一个危险因素，我们研究了EGCG是否也通过IL-12依赖的DNA修复机制预防UVB诱导的光致癌作用。为了研究这种可能性，我们以环丁烷嘧啶二聚体（CPD）的形成作为UVB诱导的DNA损伤程度的指标，测定了EGCG对IL-12基因敲除（KO）小鼠光致癌作用的影响。局部应用EGCG（1mg/cm²皮肤）在肿瘤发生率和肿瘤多发性方面可预防野生型（C3H/HeN）小鼠的光致癌作用，但不能预防IL-12 KO小鼠的光致癌作用。通过CPD的形成和晒伤细胞数量确定的UVB诱导的DNA损伤，在用EGCG处理的野生型小鼠皮肤中比未处理的对照小鼠更快得到修复。相比之下，在用EGCG处理的IL-12 KO小鼠和未处理的对照小鼠中，UVB诱导的DNA损伤程度和晒伤细胞数量没有显著差异。此外，用EGCG处理XPA功能正常的人成纤维细胞以剂量依赖的方式促进了UVB诱导的CPD的修复，但在XPA缺陷细胞中则不然，这表明核苷酸切除修复机制参与了EGCG介导的DNA修复。综上所述，这些结果首次表明EGCG可通过EGCG诱导的IL-12依赖的DNA修复机制预防光致癌作用。
