Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites.
Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites.
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DOI：
10.1007/s00726-013-1559-0
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发表时间：
2014-03
期刊：
影响因子：
3.5
通讯作者：
Gilmour SK
中科院分区：
文献类型：
--
作者：
Hayes CS;DeFeo-Mattox K;Woster PM;Gilmour SK
多胺生物合成的调节酶鸟氨酸脱羧酶(ODC)在单次亚阈值剂量的二甲基苯并(A)菲(DMBA)作用下，针对表皮的表达增加足以促进皮肤肿瘤的发展。由于皮肤肿瘤的发生涉及含有遗传损伤的毛囊隆起干细胞的募集，我们评估了增加表皮ODC对ODC-ER转基因小鼠隆起干细胞募集的影响，在ODC-ER转基因小鼠中，ODC活性在成人皮肤中被4-羟基他莫昔芬(4OHT)从头开始诱导。溴脱氧尿嘧啶核苷脉冲标记和K15CrePR1；R26R；ODC-ER三重转基因小鼠的应用表明，诱导ODC活性足以在静止的皮肤中招募隆起干细胞。由于ODC活性的增加不仅刺激增殖，而且通过随后诱导多胺分解代谢氧化酶增加活性氧物种(ROS)的产生，我们使用多胺分解代谢氧化酶活性抑制剂MDL72527来研究在DMBA启动的ODC-ER转基因皮肤中ROS的产生是否有助于皮肤肿瘤的发生。新生的ODC-ER转基因小鼠和它们的正常产仔用单次局部剂量的DMBA启动。为了评估具有DMBA启动突变的休眠隆起干细胞起源的肿瘤的发展，在DMBA启动后5周用4OHT诱导ODC-ER小鼠表皮ODC活性，然后用MDL72527治疗。MDL72527治疗可缩短肿瘤潜伏期，增加肿瘤负担，增加肿瘤转化率，降低肿瘤P53水平。因此，表皮ODC活性的升高是通过刺激隆起干细胞的募集来促进肿瘤的发生，而不是通过多胺分解代谢氧化酶产生ROS来促进肿瘤的发生。
Elevated expression of ornithine decarboxylase (ODC), the regulatory enzyme in polyamine biosynthesis, targeted to the epidermis is sufficient to promote skin tumor development following a single subthreshold dose of dimethylbenz(a)anthracene (DMBA). Since skin tumor promotion involves recruitment of hair follicle bulge stem cells harboring genetic lesions, we assessed the effect of increased epidermal ODC on recruitment of bulge stem cells in ODC-ER transgenic mice in which ODC activity is induced de novo in adult skin with 4-hydroxytamoxifen (4OHT). Bromodeoxyuridine-pulse labeling and use of K15.CrePR1;R26R;ODC-ER triple transgenic mice demonstrated that induction of ODC activity is sufficient to recruit bulge stem cells in quiescent skin. Because increased ODC activity not only stimulates proliferation but also increases reactive oxygen species (ROS) generation via subsequent induction of polyamine catabolic oxidases, we used an inhibitor of polyamine catabolic oxidase activity, MDL72527, to investigate whether ROS generation by polyamine catabolic oxidases contributes to skin tumorigenesis in DMBA-initiated ODC-ER transgenic skin. Newborn ODC-ER transgenic mice and their normal littermates were initiated with a single topical dose of DMBA. To assess tumor development originating from dormant bulge stem cells that possess DMBA-initiated mutations, epidermal ODC activity was induced in ODC-ER mice with 4OHT 5 weeks after DMBA initiation followed by MDL72527 treatment. MDL72527 treatment resulted in a shorter tumor latency time, increased tumor burden, increased conversion to carcinomas, and lower tumor levels of p53. Thus, elevated epidermal ODC activity promotes tumorigenesis by stimulating the recruitment of bulge stem cells but not via ROS generation by polyamine catabolic oxidases.
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影响因子：
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