Arecoline induces epithelial-mesenchymal transformation and promotes metastasis of oral cancer by SAA1 expression,Cancer Science

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Arecoline induces epithelial-mesenchymal transformation and promotes metastasis of oral cancer by SAA1 expression
Cancer Science ( IF 4.5 ) Pub Date : 2021-02-24 , DOI: 10.1111/cas.14866
Hui Ren ₁ , Guoqin He ₂ , Zhiyuan Lu ₃ , Qianting He ₁ , Shuai Li ₁ , Zhexun Huang ₁ , Zheng Chen ₄ , Congyuan Cao ₁ , Anxun Wang ₁

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Arecoline, the main alkaloid of areca nut, is well known for its role in inducing submucosal fibrosis and oral squamous cell carcinoma (OSCC), however the mechanism remains unclear. The aim of this study was to establish an arecoline-induced epithelial-mesenchymal transformation (EMT) model of OSCC cells and to investigate the underlying mechanisms. CAL33 and UM2 cells were induced with arecoline to establish an EMT cell model and perform RNA-sequence screening. Luminex multiplex cytokine assays, western blot, and RT-qPCR were used to investigate the EMT mechanism. Arecoline at a concentration of 160 μg/ml was used to induce EMT in OSCC cells, which was confirmed using morphological analysis, transwell assays, and EMT marker detection. RNA-sequence screening and Luminex multiplex cytokine assays showed that many inflammatory cytokines (such as serum amyloid A1 [SAA1], interleukin [IL]-6, IL-36G, chemokine [CCL]2, and CCL20) were significantly altered during arecoline-induced EMT. Of these cytokines, SAA1 was the most highly upregulated. SAA1 overexpression induced EMT and promoted the migration and invasion of CAL33 cells, while SAA1 knockdown attenuated arecoline-induced EMT. Moreover, arecoline enhanced cervical lymph node metastasis in an orthotopic xenograft model of the tongue established using BALB/c nude mice. Our findings revealed that arecoline induced EMT and enhanced the metastatic capability of OSCC by the regulation of inflammatory cytokine secretion, especially that of SAA1. Our study provides a basis for understanding the mechanism of OSCC metastasis and suggests possible therapeutic targets to prevent the occurrence and development of OSCC associated with areca nut chewing.

中文翻译：

槟榔碱通过SAA1表达诱导上皮间质转化并促进口腔癌转移

槟榔的主要生物碱槟榔碱因其在诱导粘膜下纤维化和口腔鳞状细胞癌 (OSCC) 中的作用而闻名，但其机制尚不清楚。本研究的目的是建立槟榔碱诱导的 OSCC 细胞上皮间质转化 (EMT) 模型并研究其潜在机制。用槟榔碱诱导CAL33和UM2细胞建立EMT细胞模型并进行RNA序列筛选。Luminex 多重细胞因子检测、蛋白质印迹和 RT-qPCR 用于研究 EMT 机制。浓度为 160 μg/ml 的槟榔碱用于诱导 OSCC 细胞中的 EMT，使用形态学分析、transwell 测定和 EMT 标记检测证实了这一点。RNA 序列筛选和 Luminex 多重细胞因子分析表明，许多炎性细胞因子（如血清淀粉样蛋白 A1 [SAA1]、白细胞介素 [IL]-6、IL-36G、趋化因子 [CCL]2 和 CCL20）在槟榔碱-诱发 EMT。在这些细胞因子中，SAA1 是最高度上调的。SAA1 过表达诱导 EMT 并促进 CAL33 细胞的迁移和侵袭，而 SAA1 敲低减弱了槟榔碱诱导的 EMT。此外，在使用 BALB/c 裸鼠建立的舌原位异种移植模型中，槟榔碱增强了颈部淋巴结转移。我们的研究结果表明，槟榔碱通过调节炎性细胞因子的分泌，尤其是 SAA1 的分泌，诱导 EMT 并增强 OSCC 的转移能力。

更新日期：2021-02-24

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