title: Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment.
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.
authors.affiliation: School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.|Department of Pharmacology & Therapeutics, Lung Health Research Centre (LHRC), The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Vannitamby
authors.affiliation: School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors.forename: Huei Jiunn
authors.initials: HJ
authors.lastname: Seow
authors.affiliation: Department of Pharmacology & Therapeutics, Lung Health Research Centre (LHRC), The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Gary
authors.initials: G
authors.lastname: Anderson
authors.affiliation: School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.|Department of Pharmacology & Therapeutics, Lung Health Research Centre (LHRC), The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.affiliation: Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Thompson
authors.affiliation: Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Steinfort
authors.affiliation: Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Irving
authors.affiliation: School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.|Department of Pharmacology & Therapeutics, Lung Health Research Centre (LHRC), The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology*
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020780:Matrix Metalloproteinase 9
keywords: Airway Epithelium; COPD ÀÜ Mechanisms; Lung Cancer