BACKGROUND Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine- derived Nitrosamines (NDNs). METHODS A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis. RESULTS Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade, promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR. CONCLUSION Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.

中文翻译：

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尼古丁诱发口腔癌变的新途径和机制。

背景技术无烟烟草 (SLT) 所含的尼古丁是有烟烟草 (SMT) 的 9 倍。尼古丁的致癌作用通过将尼古丁转化为尼古丁衍生的亚硝胺 (NDN) 来增强。方法 采用量身定制的搜索策略对文献进行回顾，以揭示尼古丁诱导的口腔致癌作用的新途径和机制。结果尼古丁和 NDNs 作为激动剂作用于烟碱乙酰胆碱受体 (nAChRs)。尼古丁通过增强脑多巴胺释放，通过 α4β2nAChR 和 α7nAChR 促进渴望。尼古丁与 nAChR 结合可促进口腔癌细胞的增殖、迁移、侵袭、化学抗性、放射抗性和转移。尼古丁与角质形成细胞上的 α7nAChR 结合触发 Ras/Raf-1/MEK1/ERK 级联，促进抗细胞凋亡和促增殖作用。此外，通过减少 p-EGFR 的核定位，尼古丁增强的转移在 nAChR 阻断下受到抑制。结论 长期暴露于尼古丁/NDN 会增强癌症刺激性 α7nAChR 并使癌症抑制性 α4β2nAChR 脱敏。由于 nAChR 决定了尼古丁的成瘾和致癌作用，因此将尼古丁指定为没有任何致癌性的成瘾剂似乎违反直觉。