TGFβ/SMAD/microRNA-486-3p Signaling Axis Mediates Keratin 17 Expression and Keratinocyte Hyperproliferation in Psoriasis
TGFβ/SMAD/microRNA-486-3p Signaling Axis Mediates Keratin 17 Expression and Keratinocyte Hyperproliferation in Psoriasis
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TGF beta/SMAD/microRNA-486-3p 信号轴介导银屑病角蛋白 17 表达和角质形成细胞过度增殖
DOI：
10.1016/j.jid.2017.06.005
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发表时间：
2017-10-01
影响因子：
6.5
通讯作者：
Wang, Gang
中科院分区：
文献类型：
--
作者：
Jiang, Man;Sun, Zhongbin;Wang, Gang
角蛋白17 （Keratin 17, K17）在银屑病病变而非健康皮肤中强烈表达，在疾病发病机制中起着至关重要的作用。银屑病中K17异常表达的机制尚未完全阐明。MicroRNAs是短的单链非编码rna，在调节基因表达中起重要作用。银屑病表现出与健康皮肤不同的特定microRNA表达谱。在本研究中，我们发现miR-486-3p在银屑病表皮中明显降低，并与银屑病面积和严重程度指数评分呈负相关。与对照组相比，其表达抑制过表达K17的角化细胞细胞系（LV K17）的K17蛋白表达并降低增殖。我们的数据表明，miR-486-3p受转化生长因子- β (TGF β)/SMAD通路的调控，可能介导TGF β处理的角质形成细胞中K17蛋白的下调。最后，银屑病表皮中TGF β受体I的表达降低，使TGF β /SMAD通路失活，导致K17过表达，细胞增殖。总之，我们的研究结果表明，角质形成细胞中的TGF β /SMAD/miR-486-3p信号轴调节K17的表达和细胞增殖。我们得出结论，银屑病表皮中miR-486-3p的缺失导致K17蛋白过表达，并参与银屑病的发病机制。因此，过表达miR-486-3p可能是银屑病的一种治疗选择。
Keratin 17 (K17) is strongly expressed in psoriatic lesions but not healthy skin, and plays a crucial role in disease pathogenesis. The mechanism of aberrant K17 expression in psoriasis has not been fully elucidated. MicroRNAs are short, single-stranded, noncoding RNAs that play important roles in regulating gene expression. Psoriasis exhibits a specific microRNA expression profile distinct from that of healthy skin. In this study, we showed that miR-486-3p was markedly reduced in psoriatic epidermis and negatively correlated with the psoriasis area and severity index score. Its expression repressed K17 protein expression and decreased proliferation in a keratinocyte cell line overexpressing K17 (LV K17) compared with controls. Our data indicated that miR-486-3p was regulated by a transforming growth factor-beta (TGF beta)/SMAD pathway and possibly mediated the downregulation of K17 protein in TGF beta-treated keratinocytes. Finally, the decreased expression of TGF beta receptor I in psoriatic epidermis inactivated the TGF beta/SMAD pathway, leading to K17 overexpression and cell proliferation. Collectively, our findings demonstrated that a TGF beta/SMAD/miR-486-3p signaling axis in keratinocytes regulated K17 expression and cell proliferation. We conclude that the loss of miR-486-3p in psoriatic epidermis leads to K17 protein overexpression and contributes to the pathogenesis of psoriasis. Overexpression of miR-486-3p may therefore be a therapeutic option for psoriasis.