Androgen Receptor Actions Modify Skin Structure and Chemical Carcinogen-induced Skin Cancer Susceptibility in Mice
Androgen Receptor Actions Modify Skin Structure and Chemical Carcinogen-induced Skin Cancer Susceptibility in Mice
复制标题
DOI：
10.1007/s12672-014-0210-1
复制
发表时间：
2015-02-01
影响因子：
3
通讯作者：
Handelsman, David J.
中科院分区：
文献类型：
--
作者：
Simanainen, Ulla;Ryan, Tegan;Handelsman, David J.
男性明显比女性更易患非黑色素瘤皮肤癌，并且雄激素受体（AR）广泛分布于皮肤中，表明雄激素通过AR起作用。因此，我们探讨了雄激素通过AR作用在实验性7，12-二甲基苯并[a]蒽（DMBA）诱导的皮肤致癌作用的易感性和皮肤结构发育的雄性和雌性小鼠中的作用。我们证明，男性性别和雄激素通过AR的作用改变了致癌物诱导的皮肤癌的易感性，但效果取决于所使用的致癌模型。在全身性DMBA暴露后，（p < 0.05）DMBA诱导的实验性皮肤癌比女性更敏感，AR失活显著延迟了两种男性的癌症检测。（可触知肿瘤的中位时间19对> 35周（野生型[WT]对AR敲除[ARKO]，p < 0.001）和雌性（27对> 35周，p = 0.008））小鼠。相比之下，DMBA/12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的多阶段局部皮肤癌发生后，AR失活保护了雄性和雌性小鼠免受DMBA诱导的皮肤癌的形成。皮肤结构也受到性别效应以及AR失活的影响，至少可以部分解释致癌模型之间的不同反应（全身与局部）。此外，AR失活修饰皮肤中的考克斯-1和考克斯-2表达，提示AR对皮肤作用的可能分子机制。最后，在对雄激素不敏感的ARKO小鼠中也观察到一些性别差异，表明雄激素以外的因素也在性别依赖性皮肤癌发生中发挥作用。
Men are significantly more susceptible to non-melanoma skin cancers than women, and the androgen receptor (AR) is widely distributed in the skin, suggesting a ro\le for androgens acting via AR. Therefore, we explored the role of androgen action via AR in susceptibility to experimental 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis and in skin structural development of male and female mice. We demonstrate that both the male gender and androgen action via AR modify the susceptibility to carcinogen-induced skin cancer, but the effect depends on the carcinogenesis model used. Following systemic DMBA exposure, males were significantly (p < 0.05) more susceptible to DMBA-induced experimental skin cancer than females and AR inactivation significantly delayed cancer detection in both male (median time to palpable tumours 19 vs. > 35 weeks (wild-type [WT] vs. AR knockout [ARKO], p < 0.001) and female (27 vs. > 35 weeks, p = 0.008)) mice. In contrast, following DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multistage local skin carcinogenesis, AR inactivation protected against formation of DMBA-induced skin cancers in both male and female mice. The skin structure was also affected by gender effect as well as the AR inactivation and could at least partly explain the different responses between the carcinogenesis models (systemic vs. topical). In addition, AR inactivation modified Cox-1 and Cox-2 expression in the skin, suggesting possible molecular mechanism for the AR effect on skin. Finally, some gender differences are observed also in ARKO mice insensitive to androgens, suggesting that factors other than androgens also play a role in gender-dependent skin carcinogenesis.