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Open AccessArticle

Smoking as an Independent Risk Factor for Hepatocellular Carcinoma Due to the α7-Nachr Modulating the JAK2/STAT3 Signaling Axis

1
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
2
Department of Surgery, Sijhih Cathay General Hospital, New Taipei City 221, Taiwan
3
Biostatistics Center, Taipei Medical University, Taipei 110, Taiwan
4
Department of Surgery, Taipei Medical University, Shuang Ho Hospital, New Taipei City 235, Taiwan
5
Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
6
International PhD Program in Medicine, Taipei Medical University, Taipei 110, Taiwan
7
Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
8
Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(9), 1391; https://doi.org/10.3390/jcm8091391
Received: 13 August 2019 / Revised: 29 August 2019 / Accepted: 3 September 2019 / Published: 5 September 2019
Background: Hepatocellular carcinoma (HCC) is a worldwide health problem. Currently, there is no effective clinical therapeutic strategy for HCC. Smoking is associated with several malignant diseases including cancers. Experimental approach: However, the impact of smoking on HCC is still unresolved. Retrospectively reviewed HCC patients diagnosed between 1 January 2010 and 31 December 2015 at Taipei Medical University-Shuang Ho Hospital (Ministry of Health and Welfare). We found that smoking was associated with a poor prognosis, especially recurrence and patient survival after curative surgery using a clinicopathological analysis. Results: Our univariate and multivariate analyses showed that the α7-nicotinic acetylcholine receptor (α7-nAChR) was an oncogene and risk factor for post-resection recurrence. The α7-nAChR was overexpressed in HCC tissues compared to their non-tumor counterparts. Silencing the α7-nAChR reduced the viability of HCC cells, suppressed cellular proliferation, attenuated migration and invasion, and diminished the tumor’s sphere-formation ability, with concurrent downregulation of expression levels of the TGR5, p-JAK2, p-STAT3 (Tyr705/Ser727), RhoA, ROCK1, MMP2, and MMP9 proteins. Furthermore, a positive correlation was found between α7-nAChR and JAK2 expressions (p = 0.01) in HCC specimens, as well as their membranous co-localization. Conclusion: Together, we demonstrated that the α7-nAChR may be an independent prognosticator of the progression and prognosis of HCC patients. These findings suggest that the α7-nAChR drives the progression and recurrence of HCC through JAK2/STAT3 signaling and is a novel target for anti-HCC therapy. View Full-Text
Keywords: hepatocellular carcinoma (HCC); cigarette smoking; nicotine; α7-nicotinic acetylcholine receptor (α7-nAChR); metastasis; recurrence; TGR5; JAK2-STAT3 signaling; CSC hepatocellular carcinoma (HCC); cigarette smoking; nicotine; α7-nicotinic acetylcholine receptor (α7-nAChR); metastasis; recurrence; TGR5; JAK2-STAT3 signaling; CSC
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MDPI and ACS Style

Li, C.-L.; Lin, Y.-K.; Chen, H.-A.; Huang, C.-Y.; Huang, M.-T.; Chang, Y.-J. Smoking as an Independent Risk Factor for Hepatocellular Carcinoma Due to the α7-Nachr Modulating the JAK2/STAT3 Signaling Axis. J. Clin. Med. 2019, 8, 1391.

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