Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan; Pathology Division, Nagoya City East Medical Center, Nagoya, Aichi, 464-8547, Japan.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA; Havlik-Wall Professor of Oncology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
Toxicology. 2018 Apr 1;398-399:31-40. doi: 10.1016/j.tox.2018.02.008. Epub 2018 Mar 6.
Tobacco smoking is a major risk factor for human cancers including urinary bladder carcinoma. Cigarette smoke inhalation in mice and orally administered nicotine in rats and mice increased urothelial cell proliferation. Nicotine, a major component of smoke, induced cell proliferation in multiple cell types in vitro. In the present study, the enhancing effects of nicotine on F344 rat bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined. Nicotine administered in drinking water for 32 weeks following 4 weeks of BBN treatment significantly increased the incidence and number of urothelial carcinomas dose-dependently. Ki67 and pSTAT3 labeling indices and expression of nicotinic acetylcholine receptor alpha 7 (nAChRα7) in non-tumor bladder urothelial lesions were significantly increased by nicotine, but the TUNEL assay for apoptosis showed no increase. In a 4 week study, inhibitors of nicotinic acetylcholine receptor decreased nicotine-induced urothelial simple hyperplasia and Ki67 labeling index in the bladder and kidney pelvis at a single cytotoxic dose of nicotine (40 ppm). Urothelial cytotoxicity with regenerative proliferation was observed by light and scanning electron microscopy. In vitro, nicotine was not cytotoxic to rat or human immortalized urothelial cells (do not express nicotine receptors) below millimolar concentrations, nor in human RT4, T24 or UMUC3 urothelial carcinoma cells (express nicotine receptors). However, nicotine slightly, but statistically significantly, increased cell proliferation at micromolar concentrations in human urothelial carcinoma cells. These data suggest that nicotine enhances urinary bladder carcinogenesis by inducing cytotoxicity with regenerative proliferation. The possible role of direct mitogenesis, involving nAChR and STAT3 signaling and of nicotine receptors requires further investigation at non-cytotoxic doses of nicotine.
吸烟是人类癌症的主要危险因素，包括膀胱癌。小鼠吸入香烟烟雾和给予大鼠和小鼠口服尼古丁均可增加尿路上皮细胞增殖。尼古丁是烟雾的主要成分之一，可在体外诱导多种细胞类型的细胞增殖。在本研究中，研究了尼古丁对 N-丁基-N-（4-羟丁基）亚硝胺（BBN）诱导的 F344 大鼠膀胱癌发生的增强作用。在 BBN 处理 4 周后，通过饮水给予尼古丁 32 周，可显著增加膀胱癌的发生率和数量，呈剂量依赖性。尼古丁可显著增加非肿瘤膀胱尿路上皮病变中的 Ki67 和 pSTAT3 标记指数和烟碱型乙酰胆碱受体α7（nAChRα7）的表达，但 TUNEL 检测显示凋亡无增加。在 4 周的研究中，烟碱型乙酰胆碱受体抑制剂降低了尼古丁在膀胱和肾盂中诱导的尿路上皮单纯性增生和 Ki67 标记指数，而尼古丁的单一细胞毒性剂量（40 ppm）。光镜和扫描电镜观察到具有再生增殖的尿路上皮细胞毒性。在体外，尼古丁在低于毫摩尔浓度时对大鼠或人永生化尿路上皮细胞（不表达尼古丁受体）没有细胞毒性，也不会对人 RT4、T24 或 UMUC3 尿路上皮癌细胞（表达尼古丁受体）产生细胞毒性。然而，在微摩尔浓度下，尼古丁略微但具有统计学意义地增加了人尿路上皮癌细胞的增殖。这些数据表明，尼古丁通过诱导具有再生增殖的细胞毒性来增强膀胱癌的发生。涉及 nAChR 和 STAT3 信号传导和尼古丁受体的直接有丝分裂作用的可能作用需要在非细胞毒性剂量的尼古丁下进一步研究。
