Role of the arecoline/YAP1/BMP4 pathway in promoting endothelial‐mesenchymal transition in oral submucous fibrosis

• Published in: Journal of oral pathology & medicine 2020-04, Vol.49 (4), p.305-310
• Main Authors: Yao, Mianfeng, Li, Jiang, Yuan, Shanshan, Zhu, Xilei, Hu, Zijie, Li, Qiulan, Cao, Ruoyan, Wang, Wenjin, Fang, Changyun
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Antigens, CD - metabolism; arecoline; Arecoline - pharmacology; BMP4; Bone morphogenetic protein 4; Bone Morphogenetic Protein 4 - metabolism; Cadherins - metabolism; Confocal microscopy; Correlation analysis; Dentistry; Epithelial-Mesenchymal Transition; Extracellular matrix; Fibrosis; Humans; Mesenchyme; Nuclear transport; oral submucous fibrosis; Oral Submucous Fibrosis - metabolism; Oral Submucous Fibrosis - pathology; siRNA; Therapeutic applications; Transcription factors; Transcription Factors - metabolism; Vimentin; Vimentin - metabolism; Western blotting; YAP1; Yes-associated protein
• ISSN: 0904-2512; 1600-0714
• DOI: 10.1111/jop.12945

Background Oral 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. Methods The 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. Results BMP4 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. Conclusions Arecoline induces EMT in OSF via the YAP1/BMP4 pathway. Thus, BMP4 could be considered as a potential therapeutic target for the treatment of OSF.