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

Abstract

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.

Development and Validation of a Machine Learning Prognostic Model for Hepatocellular Carcinoma Recurrence After Surgical Resection

“…In the current study, we found that smoking was associated with a recurrence risk of 2 to 3 and 3 to 5 years after HCC. The underlying mechanism might be that nicotine increases the expression of α-7-nicotinic acetylcholine receptor (α-7-nAChR), leading to recurrence through the JAK2/STAT3 signaling pathway ( 46 ). A previous study found that the history and amount of smoking were both risk factors for the progressive recurrence of HBV-related HCC ( 47 ).…”

Picroside II Improves Severe Acute Pancreatitis-Induced Hepatocellular Injury in Rats by Affecting JAK2/STAT3 Phosphorylation Signaling

“…BAX and cleaved caspase 3 are widely reported apoptotic factors [ 30 ], and JAK2/STAT3 are potent pathway mediating inflammatory responses in the SAP-induced hepatocellular injury model [ 31 ]. For apoptotic factors, after the establishment of the SAP-induced hepatocellular injury model, relative mRNA levels of BAX increased at 6 hours, 12 hours, and 24 hours ( Figure 5(a) , P < 0.05) when compared with those in the SG group.…”

The Natural Compound Dehydrocrenatidine Attenuates Nicotine-Induced Stemness and Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma by Regulating a7nAChR-Jak2 Signaling Pathways

“…Our previous study highlighted smoking as an independent risk factor for HCC progression through α 7nAChR and JAK2 signaling. [ 16 ]. In this study, we investigated the mechanisms underlying nicotine's effects on HCC progression through α 7nAChR and JAK2 signaling and the reversal of those effects by DHCT, a novel kinase inhibitor.…”

“…In the previous study by our group, we demonstrated by applying the HCC patient's clinical samples that smoking is an independent risk factor for HCC progression through the α 7nAChR and JAK2 signalling [ 16 ]. In the cholinergic system, α 7nAChRs facilitates many different pathways, it is extensively studied in association with the anti-inflammatory pathways [ 17 ].…”