α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

Chen, Xiaowei; Jia, Yanfei; Zhang, Yujie; Zhou, Dajie; Sun, Hongchen

doi:10.1111/jcmm.14941

Cited by 22 publications

(20 citation statements)

References 48 publications

(100 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We demonstrated that α5-nAChR increased EGFR phosphorylation at Y1068, as well as the downstream signaling of EGFR such as STAT3 phosphorylation at Y705 and Akt phosphorylation at S473, which has been linked to cell survival and migration [44]. Consistently, a recent report also demonstrated the involvement of α5-nAChR in the EMT process and tumor metastasis through regulating the Jab1/Csn5 signaling in lung cancer [45]. Another study revealed the role of α5-nAChR in regulating cell proliferation and migration in melanoma cells [46].…”

Section: Discussionsupporting

confidence: 85%

Low-Dose Nicotine Activates EGFR Signaling via α5-nAChR and Promotes Lung Adenocarcinoma Progression

Wang

Hsu

Liu

et al. 2020

IJMS

View full text Add to dashboard Cite

Nicotine in tobacco smoke is considered carcinogenic in several malignancies including lung cancer. The high incidence of lung adenocarcinoma (LAC) in non-smokers, however, remains unexplained. Although LAC has long been less associated with smoking behavior based on previous epidemiological correlation studies, the effect of environmental smoke contributing to low-dose nicotine exposure in non-smoking population could be underestimated. Here we provide experimental evidence of how low-dose nicotine promotes LAC growth in vitro and in vivo. Screening of nicotinic acetylcholine receptor subunits in lung cancer cell lines demonstrated a particularly high expression level of nicotinic acetylcholine receptor subunit α5 (α 5-nAChR) in LAC cell lines. Clinical specimen analysis revealed up-regulation of α 5-nAChR in LAC tumor tissues compared to non-tumor counterparts. In LAC cell lines α 5-nAChR interacts with epidermal growth factor receptor (EGFR), positively regulates EGFR pathway, enhances the expression of epithelial-mesenchymal transition markers, and is essential for low-dose nicotine-induced EGFR phosphorylation. Functionally, low-dose nicotine requires α 5-nAChR to enhance cell migration, invasion, and proliferation. Knockdown of α 5-nAChR inhibits the xenograft tumor growth of LAC. Clinical analysis indicated that high level of tumor α 5-nAChR is correlated with poor survival rates of LAC patients, particularly in those expressing wild-type EGFR. Our data identified α 5-nAChR as an essential mediator for low-dose nicotine-dependent LAC progression possibly through signaling crosstalk with EGFR, supporting the involvement of environmental smoke in tumor progression in LAC patients.

show abstract

Section: Discussionsupporting

confidence: 85%

Low-Dose Nicotine Activates EGFR Signaling via α5-nAChR and Promotes Lung Adenocarcinoma Progression

Wang

Hsu

Liu

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…In humans, allelic variation in the α5 subunit reduces α4β2α5 nAChR function and is associated with an increased vulnerability for lung cancer ( Kuryatov et al, 2011 ; Li et al, 2011 ). Nicotine activation of α5-containing nAChRs in non-small cell lung cancer leads to downstream activation of several pathways that promote cancerous proliferation and metastasis, such as JAK2/STAT3, HIF-1α/VEGF and Jab1/Csn5, as demonstrated in vitro ( Chen et al, 2020a ; Ma et al, 2014 ; Sun and Ma, 2015 ; Sun et al, 2017 ; Zhang et al, 2017 ). Further, shRNA-mediated knockdown of the α5 nAChR subunit appears to inhibit lung tumor growth in vivo ( Sun et al, 2017 ).…”

Section: Discussionmentioning

confidence: 93%

E-cigarette vape and lung ACE2 expression: Implications for coronavirus vulnerability

Lallai

Manca

Fowler

2021

Environmental Toxicology and Pharmacology

View full text Add to dashboard Cite

Evidence in humans suggests a correlation between nicotine smoking and severe respiratory symptoms with COVID-19 infection. In lung tissue, angiotensin-converting enzyme 2 (ACE2) appears to mechanistically underlie viral entry. Here, we investigated whether e-cigarette vapor inhalation alters ACE2 and nicotinic acetylcholine receptor (nAChR) expression in male and female mice. In male lung, nicotine vapor inhalation induced a significant increase in ACE2 mRNA and protein, but surprisingly, these differences were not found in females. Further, both vehicle and nicotine vapor inhalation downregulated α5 nAChR subunits in both sexes, while differences were not found in α7 nAChR subunit expression. Finally, blood ACE2 levels did not differ with exposure, indicating that blood sampling is not a sufficient indicator of lung ACE2 changes. Together, these data indicate a direct link between e-cigarette vaping and increased ACE2 expression in male lung tissue, which thereby reveals an underlying mechanism of increased vulnerability to coronavirus infection in individuals vaping nicotine.

show abstract

“…As a downstream mechanism for α5 nAChR in nicotine-induced lung cancer, JAK2/STAT3 has been identified [ 94 ]. More recently it was also shown that Jab1/Csn5 expression was correlated with α5 nAChR expression in lung cancer and that it increased the expression of N-cadherin and vimentin, which is indicative for an induction of epithelial-mesenchymal transition [ 95 ]. Taken together, these studies show that inhibiting α5 nAChR might represent a promising target for therapy for nicotine-induced non-small cell lung cancer.…”

Section: The Role Of Nicotinic Acetylcholine Receptors In Lung Cancermentioning

confidence: 99%

Nicotinic Acetylcholine Receptors in the Respiratory Tract

Hollenhorst

Krasteva‐Christ

2021

Molecules

View full text Add to dashboard Cite

Nicotinic acetylcholine receptors (nAChR) are widely distributed in neuronal and non-neuronal tissues, where they play diverse physiological roles. In this review, we highlight the recent findings regarding the role of nAChR in the respiratory tract with a special focus on the involvement of nAChR in the regulation of multiple processes in health and disease. We discuss the role of nAChR in mucociliary clearance, inflammation, and infection and in airway diseases such as asthma, chronic obstructive pulmonary disease, and cancer. The subtype diversity of nAChR enables differential regulation, making them a suitable pharmaceutical target in many diseases. The stimulation of the α3β4 nAChR could be beneficial in diseases accompanied by impaired mucociliary clearance, and the anti-inflammatory effect due to an α7 nAChR stimulation could alleviate symptoms in diseases with chronic inflammation such as chronic obstructive pulmonary disease and asthma, while the inhibition of the α5 nAChR could potentially be applied in non-small cell lung cancer treatment. However, while clinical studies targeting nAChR in the airways are still lacking, we suggest that more detailed research into this topic and possible pharmaceutical applications could represent a valuable tool to alleviate the symptoms of diverse airway diseases.

show abstract

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

Cited by 22 publications

References 48 publications

Low-Dose Nicotine Activates EGFR Signaling via α5-nAChR and Promotes Lung Adenocarcinoma Progression

Low-Dose Nicotine Activates EGFR Signaling via α5-nAChR and Promotes Lung Adenocarcinoma Progression

E-cigarette vape and lung ACE2 expression: Implications for coronavirus vulnerability

Nicotinic Acetylcholine Receptors in the Respiratory Tract

Contact Info

Product

Resources

About