Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2
Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2
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DOI：
10.1158/0008-5472.can-06-0300
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Kong, Ah-Ng Tony
中科院分区：
文献类型：
--
作者：
Xu, Changjiang;Huang, Mou-Tuan;Kong, Ah-Ng Tony
萝卜硫酸酯是一种饮食异硫氰酸酯，通过转录因子核因子E2相关因子2(NRF2)诱导细胞解毒/抗氧化酶，具有强大的化学预防作用。为了研究与Nrf2调控相关的致癌机制，我们检测了Nrf2野生型(+/+)和Nrf2基因敲除(-/-)小鼠的肿瘤发病率和每只小鼠的肿瘤数量。7，12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorhol-13-acetate治疗导致两种基因型小鼠皮肤肿瘤发生率和肿瘤数量增加；然而，与NRF2(+/+)小鼠相比，NRF2(-/-)小鼠的这两个指数明显更高。Western印迹分析表明，Nrf2和受Nrf2调控的血红素氧合酶-1在这两种基因型的小鼠皮肤肿瘤中均不表达，而在非肿瘤皮肤样本中，Nrf2(+/+)小鼠的HO-1的表达明显高于Nrf2(-/-)小鼠。接下来，我们研究了萝卜硫素对这两种基因型鼠的化学预防效果。与赋形剂治疗组相比，在7，12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate应用前14天，每天局部应用100nmoL萝卜硫素可降低NRF2(+/+)小鼠皮肤肿瘤的发生率。重要的是，在NRF2(-/-)小鼠组中，萝卜硫素预处理没有引起化学保护作用。综上所述，我们的结果首次表明，Nrf2(-/-)小鼠更容易发生皮肤肿瘤，萝卜硫素的化学预防作用至少部分是通过Nrf2介导的。
Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2-related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (-/-) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorhol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(-/-) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(-/-) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(-/-) mice group. Taken together, our results show for the first time that Nrf2(-/-) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2.