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

Abstract

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.

Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

“…Studies have pointed out that EMT signaling pathway is an important mechanism for the development of ovarian tumor [5,29]. Studies have shown that the BMP4-mediated signaling pathway led to morphological changes in tumor cells and enhanced cell adhesion, migration, and invasion by inducing EMT [30]. The EGFR signaling pathway inhibits the expression of miR-125a through the transcription factor PEA3, thereby promoting EMT and leading the poor prognosis [31].…”

Identification of novel biomarkers and candidate small molecule drugs in rheumatoid arthritis and osteoarthritis based on bioinformatics analysis of high-throughput data

“…Recently research investigated the potential pharmacological and toxic effects of arecoline [26,27]. The main toxic effects of arecoline are oral submucous fibrosis (OSF), oral squamous cell carcinoma (OSCC) and genotoxicity [28][29][30]. Cefamandole has been recommended in empiric therapy for patients with community-acquired pneumonia and as a prophylactic agent for patients receiving various surgical procedures [31].…”

The Protective Effect of Antioxidants in Areca Nut Extract-Induced Oral Carcinogenesis

“…However, AN-induced EMT has been studied in cancer progression, rather than in normal physiological processes. Arecoline, the component of AN-extract, can induce EMT, thereby exacerbating cancer progression (Zheng et al, 2018;Chang et al, 2019;Yao et al, 2019). Thus, AN-induced EMT is implicated in the primary mechanisms by which epithelial cancer cells acquire malignant phenotypes that promote metastasis.…”