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

Abstract

BackgroundCOPD 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).MethodsUsing 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.ResultsThe 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).ConclusionPGAM5 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5140-9) contains supplementary material, which is available to authorized users.

Illuminating histidine phosphorylation in the pancreatic tumor microenvironment

“…Regulators and substrates of His phosphorylation have been previously linked to roles in tumorigenesis (ACLY(Carrer et al, 2019; Shah et al, 2016), LHPP(Hou et al, 2020; Li et al, 2019; Sun et al, 2020; Wang et al, 2021; F. Wu et al, 2020; Zhang et al, 2020; Zheng et al, 2018), PGAM5(Cheng et al, 2018; Ng Kee Kwong et al, 2018)), and metastasis (ACLY(Wen et al, 2019), PHPT1(Xu et al, 2010), PGAM5(Kang et al, 2015), NME1(Kantor et al, 1993; Khan et al, 2019; Lee et al, 2018; Steeg et al, 1988; Suzuki et al, 2004)) and localize to varying subcellular regions, based upon data from this study and previous publications (detailed in Table 1). Analyzing these proteins and pHis signals in mouse pancreatic tumors, we found that pHis signals were decreased as compared to normal pancreatic tissue and non-tumor or stromal cells.…”

Recent evidence from omic analysis for redox signalling and mitochondrial oxidative stress in COPD

“…Macrophage PGAM5 levels trended towards being greater at the periphery of the cancer in patients with COPD. Together these data suggest that PGAM5 expression is associated with patient mortality and that this may be linked to abnormal mitochondrial function in specific subsets of macrophages [21].…”

“…The development of non-small cell lung carcinoma is increased in COPD patients and their disease has a worse prognosis [21]. Carcinogenesis is driven, at least in part, by abnormal mitochondrial function enhanced oxidative stress and the expression of phosphoglycerate mutase family member 5 (PGAM5), a mitophagy regulator, was highly expressed by alveolar macrophages from COPD patients and in malignant and pre-neoplastic epithelial cells [21]. Macrophage PGAM5 levels trended towards being greater at the periphery of the cancer in patients with COPD.…”

Landscape of Genetic and Modular Networks Between Non-Small Cell Lung Cancer and Chronic Obstructive Pulmonary Disease

“…Chronic obstructive pulmonary disease (COPD) also has a high prevalence and mortality rates [2] . The association between COPD and the NSCLC, including gene pathogenicity, endothelial cell remodeling and in ammatory mechanisms, has been observed in multiple studies, [3,4] .…”