Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice

Allyson K. Martínez, Kendal Jensen, Chad Hall, April O'Brien, Laurent Ehrlich, Tori White, Fanyin Meng, Tianhao Zhou, John Greene, Francesca Bernuzzi, Pietro Invernizzi, David E. Dostal, Terry Lairmore, Gianfranco Alpini, Shannon S. Glaser

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1093-1105
Number of pages13
JournalAmerican Journal of Pathology
Volume187
Issue number5
DOIs
StatePublished - May 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Martínez, A. K., Jensen, K., Hall, C., O'Brien, A., Ehrlich, L., White, T., Meng, F., Zhou, T., Greene, J., Bernuzzi, F., Invernizzi, P., Dostal, D. E., Lairmore, T., Alpini, G., & Glaser, S. S. (2017). Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice. American Journal of Pathology, 187(5), 1093-1105. https://doi.org/10.1016/j.ajpath.2017.01.011