Role of the arecoline/YAP1/BMP4 pathway in promoting endothelial-mesenchymal transition in oral submucous fibrosis
Role of the arecoline/YAP1/BMP4 pathway in promoting endothelial-mesenchymal transition in oral submucous fibrosis
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槟榔碱/YAP1/BMP4通路在促进口腔粘膜下纤维化内皮间质转化中的作用
DOI：
10.1111/jop.12945
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发表时间：
2020
影响因子：
3.3
通讯作者：
Fang Changyun
中科院分区：
文献类型：
--
作者：
Yao Mianfeng;Li Jiang;Yuan Shanshan;Zhu Xilei;Hu Zijie;Li Qiulan;Cao Ruoyan;Wang Wenjin;Fang Changyun
口腔粘膜下纤维性变（oral submucous fibrosis，OSF）是一种以上皮间质转化（epithelial-mesenchymal transition，EMT）为特征的潜在恶性病变。骨形态发生蛋白4（BMP 4）促进纤维化疾病中的EMT，但其潜在机制及其在OSF中的潜在作用尚不清楚。本研究探讨BMP 4是否在OSF的发病机制中发挥作用并探讨其潜在的mechanism. MethodsBMP 4和EMT蛋白E‐cadherin和vimentin的表达通过免疫组织化学染色在OSF标本进行了研究。采用Pearson相关分析探讨BMP 4与EMT标志物的相关性。Western blotting和RT-PCR检测用于分析槟榔碱（OSF中一种已知的EMT促进致病因子）对BMP 4的影响，并确定涉及的转录因子。共聚焦显微镜用于观察鉴定的转录因子Yes相关蛋白1（YAP 1）的细胞内亚定位。结果BMP 4在OSF中过表达，与E-cadherin和vimentin的表达相关，在EMT中起一定作用。槟榔碱通过激活YAP 1（通过其核转位）诱导BMP 4表达。此外，YAP 1/BMP 4机制是槟榔碱诱导EMT的主要分子事件，因为BMP 4表达的敲低影响EMT标志物的表达并抑制细胞外基质积聚。因此，BMP 4可能被认为是治疗OSF的潜在治疗靶点。
BackgroundOral submucous fibrosis (OSF) is a potentially malignant lesion characterized by epithelial‐mesenchymal transition (EMT). Bone morphogenetic protein 4 (BMP4) promotes EMT in fibrotic diseases, but the underlying mechanisms and its potential role in OSF are unclear. This study investigates whether BMP4 plays a role in the pathogenesis of OSF and explores the underlying mechanisms.MethodsThe expression of BMP4 and the EMT proteins E‐cadherin and vimentin was investigated in OSF specimens by immunohistochemical staining. Pearson's correlation analysis was conducted to explore the correlation between BMP4 and the EMT markers. Western blotting and RT‐PCR assays were used to analyze the effect of arecoline (a known EMT‐promoting pathogenic factor in OSF) on BMP4 and identify the transcription factor involved. Confocal microscopy was used to observe the intracellular sublocalization of the identified transcription factor, Yes‐associated protein 1 (YAP1). Finally, siRNA silencing of BMP4 was used to determine its effect on YAP1 activation and arecoline‐induced EMT.ResultsBMP4 is overexpressed in OSF and plays a role in EMT, as its expression correlates with the expression of E‐cadherin and vimentin. Arecoline induces BMP4 expression via the activation of YAP1 (through its nuclear translocation). Furthermore, the YAP1/BMP4 mechanism is the main molecular event in arecoline‐induced EMT, as knockdown of BMP4 expression affects expression of the EMT markers and inhibits extracellular matrix accumulation.ConclusionsArecoline induces EMT in OSF via the YAP1/BMP4 pathway. Thus, BMP4 could be considered as a potential therapeutic target for the treatment of OSF.