Cigarette smoke-induced malignant transformation via STAT3 signalling in pulmonary epithelial cells in a lung-on-a-chip
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RESEARCH ARTICLE
Cigarette smoke‑induced malignant transformation via STAT3 signalling in pulmonary epithelial cells in a lung‑on‑a‑chip model Wei Hou1,2 · Siyi Hu1 · Ken‑tye Yong3 · Jie Zhang2 · Hanbin Ma1 Received: 21 February 2020 / Accepted: 3 August 2020 © Zhejiang University Press 2020
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. Keyword Cigarette smoke · Microfluidic chips · STAT3 · Chronic obstructive pulmonary disease Abbreviations NSCLC Non-small cell lung cancer COPD Chronic obstructive pulmonary disease Wei Hou and Siyi Hu contribute equally to this article. * Jie Zhang [email protected] * Hanbin Ma [email protected] 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
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
3
School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore 639798, Singapore
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 trans
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