All-trans retinoic acid-induced hyaluronan production and hyperplasia are partly mediated by EGFR signaling in epidermal Keratinocytes
All-trans retinoic acid-induced hyaluronan production and hyperplasia are partly mediated by EGFR signaling in epidermal Keratinocytes
复制标题
DOI：
10.1038/sj.jid.5701098
复制
发表时间：
2008-04-01
影响因子：
6.5
通讯作者：
Tammi, Raija H.
中科院分区：
文献类型：
--
作者：
Pasonen-Seppanen, Sanna M.;Maytin, Edward V.;Tammi, Raija H.
全反式维甲酸(RA)通过尚未完全了解的机制影响表皮分化和引起角质形成细胞的过度增殖，但可能涉及调节基质分子透明质酸。本工作在器官培养和单层培养的大鼠表皮角质形成细胞(REK)上观察了全反式维甲酸对表皮形态和透明质酸代谢的影响。全反式RA处理器官型REK细胞10天后，透明质酸合成增加，透明质酸合成酶Has2和Has3表达增加，CD44受体表达增加，并伴有表皮增生。(1)EGFR抑制剂AG1478；(2)MAPK/ERK激酶抑制剂UO126；(3)基质金属蛋白酶抑制剂GM6001可阻断全反式RA诱导的细胞增殖和透明质酸的产生。这些作用与全反式维甲酸上调肝素结合的表皮生长因子样生长因子mRNA表达，增加EGFR和细胞外信号调节激酶1/2(ERK1/2)的磷酸化的结果一致。有趣的是，EGFR和ERK1/2在全反式RA治疗30分钟后就已经被激活，这表明该信号通路的激活是对全反式RA的主要反应。这些结果表明，全反式维甲酸对角质形成细胞增殖和透明质酸合成的影响部分是通过EGFR信号转导的。
All-trans retinoic acid (RA) compromises epidermal differentiation and causes keratinocyte hyperproliferation through mechanisms not completely understood, but may involve the regulatory matrix molecule hyaluronan. In this work, the influences of all-trans RA on epidermal morphology and hyaluronan metabolism were examined in organotypic and monolayer cultures of rat epidermal keratinocytes (REKs). All-trans RA treatment of organotypic REK cultures (10 days) increased the synthesis of hyaluronan, the expression of hyaluronan synthases Has2 and Has3, and the CD44 receptor, with hyperplasia of the epidermis. The hyperplasia and hyaluronan production induced by all-trans RA were blocked with (1) AG1478, an inhibitor of the EGFR; (2) UO126, an inhibitor of the MAPK/ ERK kinase, and (3) GM6001, an inhibitor of the matrix metalloproteinases. These effects were consistent with the findings that all-trans RA upregulated heparin-binding epidermal growth factor-like growth factor mRNA expression and increased the phosphorylation of EGFR and extracellular signalregulated kinase 1/ 2 (ERK1/ 2). Interestingly, the activation of EGFR and ERK1/ 2 was seen already 30 minutes after all-trans RA treatment, suggesting that the activation of this signaling pathway is a primary response to all-trans RA. These results indicate that the effects of all-trans RA on keratinocyte proliferation and hyaluronan synthesis are partly mediated through EGFR signaling.