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PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD)

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Title: PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD)
Authors: Ng Kee Kwong, F
Nicholson, A
Pavlidis, S
Adcock, I
Chung, KF
Item Type: Journal Article
Abstract: Background: COPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC). Methods Using a transcriptomic database and outcome data of 3553 NSCLC samples, we selected mitochondrial-related genes whose levels in the tumour correlated with patient mortality. We further selected those genes showing a ≥ 2 fold expression in cancer compared to normal tissue. Cell-type specific expression of these proteins in lung tissue from NSCLC patients who were non-smokers or smokers with or without COPD (healthy smokers) was determined by immunohistochemistry. Gene set variation analysis was used in additional NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures within lung cancer tissue. Results The expression of 14 mitochondrial-related genes was correlated with patient mortality and these were differentially expressed between cancer and normal lung tissue. We studied further the expression of one of these genes, PGAM5 which is a regulator of mitochondrial degradation by mitophagy. In background lung tissue, PGAM5 was only expressed in alveolar macrophages, with the highest expression in smokers with COPD compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer expressed PGAM5. Pre-neoplastic epithelium also showed the expression of PGAM5. There was no difference in expression in cancer tissue between COPD, healthy smoker and non-smoker groups. Macrophages at the edge of the cancer from COPD patients showed a trend towards higher expression of PGAM5 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and the level of expression of 9 out of 49 previously-defined macrophage transcriptomic signatures with a particular one associated with patient mortality (p<0.05). Conclusion PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and patient mortality may be mediated through the induction of specific macrophage phenotypes.
Issue Date: 10-Dec-2018
Date of Acceptance: 27-Nov-2018
URI: http://hdl.handle.net/10044/1/66535
DOI: https://dx.doi.org/10.1186/s12885-018-5140-9
ISSN: 1471-2407
Publisher: BioMed Central
Journal / Book Title: BMC Cancer
Volume: 18
Copyright Statement: © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 093080/Z/10/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Mitochondrion
Lung cancer
PGAM5 macrophage
Patient survival
EMPHYSEMA
MITOPHAGY
RISK
PHOSPHATASE
PROGNOSIS
SURVIVAL
IMPACT
GENES
SEX
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Article Number: ARTN 1238
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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