槟榔及其主要成分槟榔被国际癌症研究机构认定为口腔癌发展的主要危险因素。槟榔提取物 (ANE) 暴露与 OPMD 进展和 OSCC 恶性转化有关。然而，ANE作用于口腔微环境中其他细胞类型促进口腔癌发生的详细机制仍不清楚。通过免疫组织化学和免疫荧光染色对与OPMD和OSCC相关的巨噬细胞进行免疫分析。进行磷酸激酶和细胞因子阵列以及蛋白质印迹以确定潜在机制。 Transwell 实验用于评估 ANE 的迁移促进作用。最后应用仓鼠模型来证实ANE的体内作用。我们报道M2巨噬细胞与口腔癌进展呈正相关。 ANE 诱导 M2 巨噬细胞分化、CREB ​​磷酸化和 VCAM-1 分泌，并增加线粒体代谢。条件培养基和来自 ANE 处理的巨噬细胞的 VCAM-1 促进口腔癌前细胞的迁移和间充质表型。体内研究表明，ANE 增强仓鼠口腔颊组织中的 M2 极化和相关信号通路。我们的研究为槟榔诱导的口腔癌发生提供了新的机制，证明槟榔促进 M2 巨噬细胞分化和分泌致癌细胞因子，这些细胞因子可严重激活口腔癌前细胞的恶性转化。© 2024。作者。

Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive.Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE.We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters.Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.© 2024. The Author(s).