The Role of FABP5 in Radiation-Induced Human Skin Fibrosis
The Role of FABP5 in Radiation-Induced Human Skin Fibrosis
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FABP5 在辐射引起的人类皮肤纤维化中的作用
DOI：
10.1667/rr14901.1
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发表时间：
2018-02-01
影响因子：
3.4
通讯作者：
Zhang, Shuyu
中科院分区：
文献类型：
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作者：
Song, Jianyuan;Zhang, Huojun;Zhang, Shuyu
辐射诱导的皮肤纤维化是辐射暴露后发生的有害的慢性疾病。辐射诱导的人类皮肤纤维化的发病机制的分子变化尚未被广泛报道。蛋白质组学的技术进步使我们能够探索辐射诱导的皮肤纤维化的生物标志物和分子发病机制，有可能扩大我们对这种疾病的理解。在这项研究中，我们比较了蛋白质表达在辐射诱导的纤维化的人皮肤和邻近的正常组织使用iTRAQ为基础的蛋白质组学技术。我们确定了186个优先表达的蛋白质（53上调和133下调）之间的放射性纤维化和正常皮肤组织。差异表达的蛋白质包括角蛋白（KRT 5、KRT 6A、KRT 16和KRT 17）、caspase-14、脂肪酸结合蛋白5（FABP 5）、SLC 2A 14和casein。通过对近端启动子的生物信息学分析，鉴定了与失调蛋白相关的共同基序和相应的转录因子，包括PAX 5、TBX 1、CLOCK和AP 2D。特别地，更详细地研究了FABP 5（在纤维化皮肤组织中增加2.15倍），一种疏水脂肪酸的转运蛋白。免疫组化证实，FABP 5的蛋白水平在纤维化的人皮肤组织中增加，特别是在表皮中。在人成纤维细胞WS 1中，FABP 5的过表达导致SMAD 2的核转位和促纤维化TGF-β信号通路的显著激活。此外，外源性FABP 5（FABP 5-EGFP）可被皮肤细胞掺入并增强TGF-β信号传导，表明微环境与皮肤纤维化之间存在联系。总之，我们的研究结果说明了辐射诱导的人类皮肤纤维化过程中的分子变化以及FABP 5在激活TGF-β信号通路中的关键作用。
Radiation-induced skin fibrosis is a detrimental and chronic disorder that occurs after radiation exposure. The molecular changes underlying the pathogenesis of radiation-induced fibrosis of human skin have not been extensively reported. Technical advances in proteomics have enabled exploration of the biomarkers and molecular pathogenesis of radiation-induced skin fibrosis, with the potential to broaden our understanding of this disease. In this study, we compared protein expression in radiation-induced fibrotic human skin and adjacent normal tissues using iTRAQ-based proteomics technology. We identified 186 preferentially expressed proteins (53 upregulated and 133 downregulated) between radiogenic fibrotic and normal skin tissues. The differentially expressed proteins included keratins (KRT5, KRT6A, KRT16 and KRT17), caspase-14, fatty acid-binding protein 5 (FABP5), SLC2A14 and resistin. Through bioinformatic analysis of the proximal promoters, common motifs and corresponding transcriptional factors were identified that associate with the dysregulated proteins, including PAX5, TBX1, CLOCK and AP2D. In particular, FABP5 (2.15-fold increase in fibrotic skin tissues), a transporter of hydrophobic fatty acids, was investigated in greater detail. Immunohistochemistry confirmed that the protein level of FABP5 was increased in fibrotic human skin tissues, especially in the epidermis. Overexpression of FABP5 resulted in nuclear translocation of SMAD2 and significant activation of the profibrotic TGF-β signaling pathway in human fibroblast WS1 cells. Moreover, exogenous FABP5 (FABP5-EGFP) could be incorporated by skin cells and intensify TGF-β signaling, indicating a communication between the microenvironment and skin fibrosis. Taken together, our findings illustrate the molecular changes during radiation-induced human skin fibrosis and the critical role of FABP5 in activating the TGF-β signaling pathway.