Glucocorticoids activate Yes-associated protein in human vocal fold fibroblasts.
Glucocorticoids activate Yes-associated protein in human vocal fold fibroblasts.
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DOI：
10.1016/j.yexcr.2021.112681
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发表时间：
2021-08-15
影响因子：
3.7
通讯作者：
Branski RC
中科院分区：
文献类型：
--
作者：
Nakamura R;Bing R;Doyle CP;Garabedian MJ;Branski RC
声带纤维化带来了实质性的临床挑战，可能是上呼吸道直接注射类固醇快速扩散的潜在原因。声带对糖皮质激素 (GC) 的不同临床反应可能与 GC 固有的多样性以及患者特异性和上游细胞特异性对 GC 的反应有关。一般来说，我们假设临床结果的差异是由于 GC 对常驻成纤维细胞的不良影响所致。转录组分析发现了 GC 介导的 Hippo 信号传导的显着调节，Hippo 信号传导是纤维化基因表达的已知调节因子。随后的分析证实了 GC 介导的 YAP 激活，这是 Hippo 信号通路中的转录辅助因子。 YAP 抑制减弱了 GC 处理的人声带成纤维细胞中 ACTA2 的表达。然而，Ser211 的核定位和磷酸化不受 YAP 抑制的影响，表明 YAP 的核转位是由 GR 间接驱动的。 RNA-seq分析证实了GC对Wnt信号传导的影响，并且GCs上调了典型的Wnt信号传导靶基因。这些数据表明 YAP 及其下游靶标是 GC 促纤维化反应的假定介质。治疗性 YAP 抑制最终可能具有临床相关性，值得进一步考虑。
Fibrosis of the vocal folds poses a substantive clinical challenge potentially underlying the rapid proliferation of direct steroid injections into the upper airway. The variable clinical response to glucocorticoids (GCs) in the vocal folds is likely related to diversity inherent to GCs and both patient-specific, and upstream, cell-specific responses to GCs. Broadly, we hypothesize the disparity in clinical outcomes are due to undesirable effects of GCs on resident fibroblasts. Transcriptome analysis identified significant GC-mediated modulation of Hippo signaling, a known regulator of fibrotic gene expression. Subsequent analysis confirmed GC-mediated YAP activation, a transcriptional co-factor in the Hippo signaling pathway. YAP inhibition attenuated ACTA2 expression in GC-treated human vocal fold fibroblasts. Nuclear localization and phosphorylation at Ser211, however, was not affected by YAP inhibition, suggesting nuclear translocation of YAP is indirectly driven by GR. RNA-seq analysis confirmed the influence of GCs on Wnt signaling, and canonical Wnt signaling target genes were upregulated by GCs. These data implicate YAP and its downstream targets as putative mediators of a pro-fibrotic response to GCs. Therapeutic YAP inhibition may ultimately be clinically relevant and warrants further consideration.
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