Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice.
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.
Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Allyson K
AK
Martínez
Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Kendal
K
Jensen
Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Chad
C
Hall
Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
April
A
O'Brien
Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Laurent
L
Ehrlich
Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Tori
T
White
Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
Fanyin
F
Meng
Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Tianhao
T
Zhou
Department of Pathology, Baylor Scott & White Health, Temple, Texas.
John
J
Greene
Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Francesca
F
Bernuzzi
Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Pietro
P
Invernizzi
Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas.
David E
DE
Dostal
Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
Terry
T
Lairmore
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; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
Gianfranco
G
Alpini
Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas. Electronic address: sglaser@medicine.tamhsc.edu.
Shannon S
SS
Glaser
D000368:Aged; D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D000071999:S100 Calcium-Binding Protein A4 / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000502:physiology
D053539:Keratin-19; D018722:Nicotinic Agonists; D000071999:S100 Calcium-Binding Protein A4; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D048049:Extracellular Signal-Regulated MAP Kinases