Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice

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.

5-Hydroxymethylome in Circulating Cell-Free DNA as A Potential Biomarker for Non-Small-Cell Lung Cancer

“…Similarly, the unbiased PCA also demonstrated distinct signatures that could separate these two groups ( Figure 4 D). KEGG functional enrichment analysis showed that up-regulated DhMGs in the lung cancer group are mainly enriched in nicotine addition, calcium signaling pathway, and circadian entrainment pathways, which are closely associated with cancer development [32] , [33] ( Figure 4 E). Genes with decreased 5hmC signal were enriched in several cancer- and metastasis-related pathways including platelet activation pathway, cGMP-PKG signaling pathway, Rap signaling pathway, and PI3K-Akt signaling pathway [34] , [35] ( Figure 4 F).…”

Nerve fibers in the tumor microenvironment in neurotropic cancer—pancreatic cancer and cholangiocarcinoma

“…Also, higher densities of muscarinic Ach receptor 3 (M3) showed an association with high-grade differentiation of PDAC, more lymph node metastasis and a shorter patient overall survival (OS) [44]. In CCA, the presence of the cholinergic system plays a role in CCA cell proliferation and growth [46,47].…”

The dual role of alpha7 nicotinic acetylcholine receptor in inflammation-associated gastrointestinal cancers

“…Similarly, it has been reported that α7nAChR is one of the predominantly expressed nicotinic receptors in both LC cell lines and primary hepatoma cells, demonstrating that these receptors may play crucial roles in the regulation of LC development and progression [9]. This receptor is more highly expressed in LC cells compared with normal cells and serves as a predominant protein responsible for nicotine-mediated LC progression [78]. Previous studies have shown the involvement of α7nAChR in liver pathological processes such as promoting carcinogenesis pathways in the liver.…”

“…Aizawa et al have shown that NNK as a high-affinity ligand of the α7nAChR through increased expression and activation of this receptor caused to hepatic damage and HCC progression in an animal model [79]. Similarly, Martínez and colleagues study suggest that nicotine acts through α7nAChR to stimulate the cholangiocyte proliferation in both in vitro and in xenograft mice model of LC [78]. In this context, the anti-tumor activity of acetylcholinesterase in HCC cells can also be justified by considering the fact that ACh is an important endogenous activator of α7nAChR [80].…”