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  • Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment

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Research letter
Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment
  1. Amanda Vannitamby1,2,
  2. Huei Jiunn Seow1,
  3. Gary Anderson2,
  4. Ross Vlahos1,2,
  5. Michelle Thompson3,
  6. Daniel Steinfort3,
  7. Louis B Irving3,
  8. Steven Bozinovski1,2
  1. 1School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
  2. 2Department of Pharmacology & Therapeutics, Lung Health Research Centre (LHRC), The University of Melbourne, Melbourne, Victoria, Australia
  3. 3Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  1. Correspondence to Dr Steven Bozinovski, School of Health & Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; steven.bozinovski{at}rmit.edu.au

Abstract

Matrix metalloproteinase-9 (MMP-9) is increased in a number of pathological lung conditions, where the proteinase contributes to deleterious remodelling of the airways. While both lung cancer and COPD are associated with increased MMP-9 expression, the cellular and molecular drivers of MMP-9 remain unresolved. In this study, MMP-9 transcript measured within the tumour region from patients with non-small-cell lung cancer (NSCLC) and coexisting COPD was found to be uniformly increased relative to adjacent tumour-free tissue. MMP-9 gene expression and immunohistochemistry identified tumour-associated neutrophils, but not macrophages, as a predominant source of this proteinase. In addition, PTEN gene expression was significantly reduced in tumour and there was evidence of epithelial MMP-9 expression. To explore whether PTEN can regulate epithelial MMP-9 expression, a small interfering (si)RNA knockdown strategy was used in Beas-2B bronchial epithelial cells. PTEN knockdown by siRNA selectively increased MMP-9 expression in response to lipopolysaccharide in a corticosteroid-insensitive manner. In summary, tumour-associated neutrophils represent an important source of MMP-9 in NSCLC, and loss of epithelial PTEN may further augment steroid-insensitive expression.

  • COPD ÀÜ Mechanisms
  • Lung Cancer
  • Airway Epithelium

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/thoraxjnl-2016-209389

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    Footnotes

    • Contributors AV and SB: responsible for generation of hypothesis and experimental design of all experiments; they conducted most of the experiments and wrote and revised the manuscript. HJS, GA, MT, LBI, RV and DS: contributed to the experimental design and data analysis and contributed to manuscript preparation.

    • Funding National Health and Medical Research Council; Australian Research Council.

    • Competing interests None declared.

    • Ethics approval Royal Melbourne Hospital Human Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.