Role of Homeodomain-Interacting Protein Kinase 2 in the Pathogenesis of Tissue Fibrosis in Keloid-Derived Keratinocytes
Role of Homeodomain-Interacting Protein Kinase 2 in the Pathogenesis of Tissue Fibrosis in Keloid-Derived Keratinocytes
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同源结构域相互作用蛋白激酶2在瘢痕疙瘩衍生角质形成细胞组织纤维化发病机制中的作用
DOI：
10.1097/sap.0000000000001243
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发表时间：
2017-12-01
影响因子：
1.5
通讯作者：
Li，Qing-Feng
中科院分区：
文献类型：
--
作者：
Zhao，Yi-Xuan;Zhang，Guo-You;Li，Qing-Feng
上皮-间质转化（Epithelial-mesenchymal transition， EMT）在纤维化瘢痕疙瘩的形成中起着关键作用，其特征是胶原过多和细胞外基质的合成和沉积。越来越多的证据表明丝氨酸/苏氨酸激酶同源结构域相互作用蛋白激酶2 （HIPK2）在几个主要纤维化信号通路的上游起作用；然而，HIPK2在瘢痕疙瘩纤维形成中的作用尚不清楚。在目前的研究中，我们研究了HIPK2在瘢痕疙瘩发病机制中的作用。培养原代正常皮肤和瘢痕疙瘩角质形成细胞，并用转化生长因子(TGF) -β1预处理。接下来，用小干扰RNA （siRNA）和抗hipk2 siRNA转染角质形成细胞。实时定量聚合酶链反应检测TGF-β1相关HIPK2的改变。western blotting分析蛋白水平。与正常皮肤角质形成细胞相比，瘢痕疙瘩源性角质形成细胞中的HIPK2明显升高。此外，HIPK2通过TGF -β1-SMAD家族成员3 （SMAD3）诱导正常皮肤角质形成细胞中EMT标志物的表达。当细胞转染HIPK2 siRNA时，TGF-β1相关EMT标记和SMAD3磷酸化对TGF-β1的影响被显著消除。我们得出结论，HIPK2是瘢痕疙瘩发病机制中的一个关键因素，表明HIPK2可能是抗瘢痕疙瘩治疗的一个新的潜在药物靶点。
Epithelial-mesenchymal transition (EMT) plays a critical role in fibrotic keloid formation, which is characterized by excessive collagen and extracellular matrix synthesis and deposition. Growing evidence suggests that the serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) acts upstream of several major fibrosis signaling pathways; however, the role of HIPK2 in the keloid fibrogenesis remains unknown. In the current study, we investigated the roles of HIPK2 in the pathogenesis of keloids. Primary normal skin and keloid keratinocytes were cultured and pretreated with transforming growth factor (TGF)–β1. Next, keratinocytes were transfected with scrambled small interfering RNA (siRNA) and anti-HIPK2 siRNA. The TGF-β1–associated HIPK2 alterations were investigated by quantitative real-time polymerase chain reaction. Protein levels were analyzed by western blotting. The HIPK2 was markedly increased in the keloid-derived keratinocytes compared with normal skin keratinocytes. In addition, HIPK2 induced the expression of EMT markers in normal skin keratinocytes by TGF-β1–SMAD family member 3 (SMAD3). The effect of TGF-β1–related EMT markers and SMAD3 phosphorylation in response to added TGF-β1 was significantly abrogated when the cells were transfected with HIPK2 siRNA. We conclude that HIPK2 is a crucial factor in the pathogenesis of keloids, suggesting that HIPK2 might be a novel potential drug target for antikeloid therapy.