槟榔致癌物质与口腔癌

Areca nut-related carcinogens and oral cancer

槟榔为一级致癌物，咀嚼槟榔引起口腔癌缘于槟榔中的槟榔碱（ARC）、槟榔鞣质、槟榔特异性亚硝胺（ASNA）和活性氧（ROS）等具有细胞毒性、遗传毒性、致突变性和致癌性。ARC可诱导口腔成纤维细胞、角质形成细胞和人脐静脉内皮细胞程序性死亡。槟榔鞣质有否遗传毒性和致突变性至今仍有争议，不同类型的短期筛选试验结果差异很大，但含鞣质的槟榔多酚是槟榔的主要致癌成分。3-甲基亚硝氨基内醛可诱发人颊黏膜角质形成细胞的DNA链断裂和DNA蛋白交联。3-甲基亚硝氨基丙腈为强致癌剂，可诱发试验动物肿瘤，靶器官包括鼻腔、食管、舌等。槟榔咀嚼过程中可产生大量的ROS，造成DNA氧化性损伤和激活癌基因的方式促使癌症的发生。相对分子质量为3．0×10^4-10．0×10^4的槟榔提取物组分中一种新发现的蛋白聚糖通过增加胞内ROS水平及一系列信号级联放大，上调口腔癌细胞低氧诱导因子-1d的表达，最终诱导细胞自噬。细胞自噬有利于保护癌细胞免遭ARC诱导的程序性细胞死亡，促进口腔癌的发展。槟榔提取物还可能通过ROS增强舌鳞状上皮细胞癌细胞株刺激血小板聚集的效应，从而促进舌癌转移。

Areca nut is a recently confirmed class I carcinogen. The areca nut chewing habit is a primary environmental risk factor for the development of oral cancer due to cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of arecoline（ARC）, areca-containing tannins, areca-specific nitrosamine（ASNA）, and reactive oxygen species（ROS） produced during areca nut chewing. ARC is capable of inducing apoptosis of oral fibroblasts, keratinocytes, and human umbilical vein endothelial cells. The results of different types of short-term screening tests differ, so the genotoxicity and mutagenicity of areca-containing tannins remain controversial. Tannin-containing polyphenolic fraction is a primary carcinogenic ingredient. 3-Methyl-nitrosamino propionaldehyde can induce DNA strand breakage and DNA-protein crosslinkage for human buccal keratinocytes. 3-Methyl-nitrosamino propionitrile is a potent carcinogen that can induce nasal, esophageal, and tongue tumors in laboratory animals. ROS produced during areca nut chewing can promote tumorigenesis by inducing DNA oxidative damage and activating oncogenes. A newly found proteoglycan in the 3.0xl04 to 10.0x 104 relative molecular mass fraction of areca nut extract induces oxidative stress and modulates a signaling cascade that upregulates hypoxia, inducing factor-lc~ expression in oral cancer cells, which eventually leads to autophagy. Autophagy can help cancer cells survive ARC-induced apoptosis and promote the development of oral cancer. Areca nut extract can enhance tongue cancer cell-induced platelet aggregation by generating ROS, thus promoting tongue cancer metastasis.