Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Am J Pathol. 2017 May;187(5):1093-1105. doi: 10.1016/j.ajpath.2017.01.011. Epub 2017 Mar 14.
Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR-dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.
尼古丁是烟草中的主要成瘾物质，已知其在多种恶性肿瘤的发生和/或进展中起作用。然而，尼古丁在胆管癌发病机制中的作用存在争议。因此，我们研究了尼古丁对胆管癌细胞体外生长和胆管癌细胞在小鼠异种移植模型中进展的影响。在人胆管癌细胞系中，尼古丁介导的增殖的主要亚基，即α7 烟碱型乙酰胆碱受体（α7-nAChR），比正常的人胆管细胞表达更高。尼古丁还刺激胆管癌细胞系的增殖，并促进 Mz-ChA-1 细胞中α7-nAChR 依赖性增殖和细胞外调节激酶磷酸化的激活。此外，尼古丁和 PNU282987（α7-nAChR 激动剂）加速了我们的异种移植小鼠模型中胆管癌肿瘤的生长，并增加了纤维化、肿瘤细胞的增殖和细胞外调节激酶的磷酸化激活。最后，α7-nAChR 在人胆管癌中的表达水平明显高于正常的人对照肝样本。总之，这项研究的结果表明，尼古丁通过α7-nAChR 起作用，并在胆管癌的发病机制中发挥新的作用。此外，尼古丁可能在胆汁淤积性肝病过程中作为有丝分裂原起作用，从而促进恶性转化。
