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Cigarette smoke-induced malignant transformation via STAT3 signalling in pulmonary epithelial cells in a lung-on-a-chip model

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Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a severe public health problem. Cigarette smoke (CS) is a risk factor for COPD and lung cancer. The underlying molecular mechanisms of CS-induced malignant transformation of bronchial epithelial cells remain unclear. In this study, we describe a lung-on-a-chip to explore the possible mechanistic link between cigarette smoke extract (CSE)-associated COPD and lung cancer.

Methods

An in vitro lung-on-a-chip model was used to simulate pulmonary epithelial cells and vascular endothelial cells with CSE. The levels of IL-6 and TNF-α were tested as indicators of inflammation using an enzyme-linked immune sorbent assay. Apical junction complex mRNA expression was detected with qRT-PCR as the index of epithelial-to-mesenchymal transition (EMT). The effects of CSE on the phosphorylation of signal transduction and transcriptional activator 3 (STAT3) were detected by Western blotting. Flow cytometry was performed to investigate the effects of this proto-oncogene on cell cycle distribution.

Results

Inflammation caused by CSE was achieved in a lung-on-a-chip model with a mimetic movement. CSE exposure induced the degradation of intercellular connections and triggered the EMT process. CSE exposure also activated the phosphorylation of proto-oncogene STAT3, while these effects were inhibited with HJC0152.

Conclusions

CSE exposure in the lung-on-a-chip model caused activation of STAT3 in epithelial cells and endothelial cells. HJC0152, an inhibitor of activated STAT3, could be a potential treatment for CS-associated COPD and lung cancer.

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Data availability

All data generated or analysed during this study are included in this published article.

Abbreviations

NSCLC:

Non-small cell lung cancer

COPD:

Chronic obstructive pulmonary disease

EGFR:

Epidermal growth factor receptor

STAT3:

Signal transduction and transcriptional activators 3

PDMS:

Polydimethylsiloxane

ICAM:

Intercellular cell adhesion molecule

CAFs:

Cancer-associated fibroblasts

IL-6:

Interleukin-6

IFP:

Interstitial fluid pressure

ZOs:

Zonula occludens

EMT:

Epithelial–mesenchymal transformation

AJC:

Apical junctional complex

VCAM:

Vascular cell adhesion molecule

α-SMA:

Alpha smooth muscle actin

VEGF:

Vascular endothelial growth factor

ALK:

Anaplasticlymphoma kinase

SOCS:

Suppressor of cytokine signalling

EndMT:

Endothelial–mesenchymal transition

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Funding

This work was supported by National Natural Science Foundation of China (Grant Nos.81672297; Grant Nos.61701493), Policy Guidance project (International Science and Technology Cooperation) of Jiangsu Province of China (BZ2018040), the Natural Science Foundation of Tianjin, P.R. China (18JCYBJC42100), Hundred Talents Program of the Chinese Academy of Sciences, Project Funded by China Postdoctoral Science Foundation (2019M651959), Postdoctoral Research Funding Program of Jiangsu Province (2018K004B).

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Author notes

  1. Wei Hou and Siyi Hu contribute equally to this article.

Authors and Affiliations

  1. CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, No.88 Keling Road, Huqiu District, Suzhou, 215163, Jiangsu, People’s Republic of China

    Wei Hou, Siyi Hu & Hanbin Ma

  2. Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, No.218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin, People’s Republic of China

    Wei Hou & Jie Zhang

  3. School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore, 639798, Singapore

    Ken-tye Yong

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  1. Wei Hou
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Contributions

W.H, S.H, J.Z. and H.M. conceived the concept and experiments. K-T. Y designed some parts of experiment. W.H. and S.Y. carried out the experiment and collected data. W.H. and S.H. wrote the manuscript, and all authors reviewed and commented on the manuscript.

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Correspondence to Jie Zhang or Hanbin Ma.

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The authors declare that they have no conflict of interest.

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No laboratory animals or tissue samples from patients were used in this study. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of The Second Hospital of Jilin University.

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Hou, W., Hu, S., Yong, Kt. et al. Cigarette smoke-induced malignant transformation via STAT3 signalling in pulmonary epithelial cells in a lung-on-a-chip model. Bio-des. Manuf. 3, 383–395 (2020). https://doi.org/10.1007/s42242-020-00092-6

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