Upregulation of miR-203 and miR-210 affect growth and differentiation of keratinocytes after exposure to sulfur mustard in normoxia and hypoxia
Upregulation of miR-203 and miR-210 affect growth and differentiation of keratinocytes after exposure to sulfur mustard in normoxia and hypoxia
复制标题
DOI：
10.1016/j.toxlet.2015.09.012
复制
发表时间：
2016-02-26
影响因子：
3.5
通讯作者：
Ries, Christian
中科院分区：
文献类型：
--
作者：
Deppe, Janina;Steinritz, Dirk;Ries, Christian
皮肤暴露于硫芥菜（SM）会导致长期并发症，如组织再生受损。先前自己对SM处理的正常人表皮角质形成细胞（NHEK）的研究表明，细胞增殖减少、过早分化和缺氧介导的信号传导功能受到限制。在这里，我们研究了microrna miR-203和miR-210在这些机制中的作用。在常氧和缺氧条件下培养时，SM显著上调NHEK中miR-203的表达。正常缺氧条件下，SM对miR-210无影响。然而，在缺氧条件下生长的NHEK中，miR-210水平大大增加，并在细胞暴露于SM后进一步升高。在常氧和缺氧条件下，通过转染互补寡核苷酸anti-miR-203的NHEK抑制miR-203，减轻了sm诱导的代谢活性和增殖损伤，并抵消了sm促进的角蛋白1在这些细胞中的表达。通过抑制miR-210在缺氧条件下生长的NHEK细胞中，sm处理的NHEK中代谢活性失调、增殖和角蛋白1表达的改善作用一致。我们的研究结果提供了证据，证明miR-203和miR-210是正常和sm损伤的角化细胞功能的关键调节因子，并表明miR-203和miR-210抑制剂在靶向治疗干预中改善sm损伤皮肤的再上皮化的潜在有效性。2015爱思唯尔爱尔兰有限公司版权所有。
Exposure of the skin to sulfur mustard (SM) results in long-term complications such as impaired tissue regeneration. Previous own studies in normal human epidermal keratinocytes (NHEK) treated with SM demonstrated reduced proliferation, premature differentiation and a restricted functionality of hypoxia-mediated signaling in the cells. Here, we investigated the involvement of microRNAs, miR-203 and miR-210, in these mechanisms. SM significantly upregulated the expression of miR-203 in NHEK when cultivated under normoxic and hypoxic conditions. SM had no effect on miR-210 under normoxia. However, miR-210 levels were greatly increased in NHEK when grown in hypoxia and further elevated upon exposure of the cells to SM. In normoxia and hypoxia, inhibition of miR-203 by transfection of NHEK with complementary oligonucleotides, anti-miR-203, attenuated the SM-induced impairment of metabolic activity and proliferation, and counteracted SM-promoted keratin-1 expression in these cells. Consistent ameliorating effects on dysregulated metabolic activity, proliferation and keratin-1 expression in SM-treated NHEK were obtained upon inhibition of miR-210 in these cells grown in hypoxia. Our findings provide evidence that miR-203 and miR-210 are key regulators in normal and SM-impaired keratinocyte functionality, and suggest potential usefulness of inhibitors against miR-203 and miR-210 for target-directed therapeutical intervention to improve re-epithelialization of SM-injured skin. (C) 2015 Elsevier Ireland Ltd. All rights reserved.