槟榔碱是槟榔中发现的主要活性致癌物,与口腔鳞状细胞癌(OSCC)和口腔粘膜下纤维化(OSF)的发病机理有关。对于这项研究,我们通过将迭代范围审查与事后搜索相结合,进行了逐步审查过程,目的是确定槟榔碱引发和促进口腔癌变的具体机制。我们的初步搜索使我们能够定义槟榔碱诱导的OSF和OSCC的病理生理学的当前趋势和模式。包括诱导细胞增殖,协助入侵,附着力,和移民,胶原蛋白沉积和纤维化增加,免疫和炎症机制失衡,和遗传毒性。关键的分子途径包括NOTCH1,MYC,PRDX2,WNT,CYR61,EGFR/Pl3K,DDR1信令,和细胞因子上调。尽管提供了OSF潜在致病机制的全面概述,作为槟榔生物碱受体的分子的参与,即,毒蕈碱和烟碱乙酰胆碱受体(AChRs),没有用这种方法阐明。因此,我们对搜索策略进行了改进,以反映这些证据差距.事后搜索的第二轮审查结果强调,槟榔碱优先与毒蕈碱AChRs结合,与癌症有关。始终如一,AChRs激活与槟榔碱诱导的致癌作用中描述的信号通路部分重叠的信号通路。总之,我们使用了一种理论驱动的解释性综述方法来告知,延伸,并补充常规的系统文献评估工作流程。一方面,这种关键的解释性合成的结果突出了当前的趋势,并使有关槟榔碱诱导的致癌作用的分子机制的数据巩固,and,另一方面,提出了与局部胆碱能轴在口腔癌发生中的作用相关的知识空白,因此建议进一步调查的领域。
Arecoline is the primary active carcinogen found in areca nut and has been implicated in the pathogenesis of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). For this study, we conducted a stepwise review process by combining iterative scoping reviews with a post hoc search, with the aim of identifying the specific mechanisms by which arecoline initiates and promotes oral carcinogenesis. Our initial search allowed us to define the current trends and patterns in the pathophysiology of arecoline-induced OSF and OSCC, which include the induction of cell proliferation, facilitation of invasion, adhesion, and migration, increased collagen deposition and fibrosis, imbalance in immune and inflammatory mechanisms, and genotoxicity. Key molecular pathways comprise the activation of NOTCH1, MYC, PRDX2, WNT, CYR61, EGFR/Pl3K, DDR1 signaling, and cytokine upregulation. Despite providing a comprehensive overview of potential pathogenic mechanisms of OSF, the involvement of molecules functioning as areca alkaloid receptors, namely, the muscarinic and nicotinic acetylcholine receptors (AChRs), was not elucidated with this approach. Accordingly, our search strategy was refined to reflect these evidence gaps. The results of the second round of reviews with the post hoc search highlighted that arecoline binds preferentially to muscarinic AChRs, which have been implicated in cancer. Consistently, AChRs activate the signaling pathways that partially overlap with those described in the context of arecoline-induced carcinogenesis. In summary, we used a theory-driven interpretive review methodology to inform, extend, and supplement the conventional systematic literature assessment workflow. On the one hand, the results of this critical interpretive synthesis highlighted the prevailing trends and enabled the consolidation of data pertaining to the molecular mechanisms involved in arecoline-induced carcinogenesis, and, on the other, brought up knowledge gaps related to the role of the local cholinergic axis in oral carcinogenesis, thus suggesting areas for further investigation.