1 Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
2 Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
J Dent Res. 2019 Jul;98(8):920-929. doi: 10.1177/0022034519851804.
Oral submucous fibrosis (OSF) is a potentially malignant disorder. Current studies have shown that chewing areca nut is considered the main cause of OSF, and endothelial-mesenchymal transformation (EndMT) participates in the occurrence and development of the fibrotic lesion. However, the specific molecular mechanisms and treatments remain unclear. Here, we report the mechanism of arecoline-induced EndMT and the importance of this mechanism in OSF, and we also identify potential therapeutics for decreasing OSF incidence. We demonstrate the overexpression of Yes-associated protein (YAP) in human samples and that it was significantly associated with OSF pathologic stage. Arecoline activated YAP by increasing reactive oxygen species levels and inducing the PERK pathway (eukaryotic translation initiation factor 2 alpha kinase 3), resulting in the initiation of EndMT and leading to OSF. Verteporfin, a YAP-TEA domain pathway inhibitor, suppressed EndMT and decreased collagen accumulation, resulting in the alleviation of OSF in mice. These data indicate that arecoline regulates the activity of YAP and highlight an alternative method for treating OSF.
口腔黏膜下纤维性变（OSF）是一种潜在的恶性疾病。目前的研究表明，咀嚼槟榔被认为是 OSF 的主要原因，内皮-间充质转化（EndMT）参与了纤维病变的发生和发展。然而，具体的分子机制和治疗方法仍不清楚。在这里，我们报告了槟榔碱诱导的 EndMT 机制及其在 OSF 中的重要性，我们还确定了降低 OSF 发病率的潜在治疗方法。我们证明了 Yes 相关蛋白（YAP）在人类样本中的过表达，并且它与 OSF 的病理阶段显著相关。槟榔碱通过增加活性氧水平和诱导 PERK 途径（真核翻译起始因子 2α激酶 3）来激活 YAP，从而引发 EndMT，并导致 OSF。YAP-TEA 结构域通路抑制剂维替泊芬抑制 EndMT 和胶原积累减少，导致小鼠 OSF 缓解。这些数据表明槟榔碱调节 YAP 的活性，并强调了治疗 OSF 的另一种方法。
