Imbalance in redox status is associated with tumor aggressiveness and poor outcome in lung adenocarcinoma patients |
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Authors: | Leonardo Lisbôa da Motta Carolina B Müller Marco A De Bastiani Guilherme A Behr Fernanda S França Ricardo F da Rocha Juliane B Minotto Rosalva T Meurer Marilda C Fernandes Adriana Roehe Melissa M Markoski Cristiano F Andrade Mauro A A Castro Fábio Klamt |
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Institution: | 1. Laboratory of Cellular Biochemistry, Department of Biochemistry (ICBS), Federal University of Rio Grande do Sul (UFRGS), 2600 Ramiro Barcelos St, Porto Alegre, RS, 90035-003, Brazil 2. National Institutes of Science and Technology – Translational Medicine (INCT-TM), Porto Alegre, RS, 90035-903, Brazil 3. Laboratory of Pathology Research, UFCSPA, Porto Alegre, RS, 90050-170, Brazil 4. Laboratory of Cellular and Molecular Cardiology, IC/FUC, Porto Alegre, RS, 90620-000, Brazil 5. Clinics Hospital of Porto Alegre (HCPA)/UFRGS, Porto Alegre, RS, 90035-903, Brazil 6. Santa Casa de Misericórdia Hospital, Porto Alegre, RS, 90020-090, Brazil
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Abstract: | Purpose The expression levels of human antioxidant genes (HAGs) and oxidative markers were investigated in light of lung adenocarcinoma aggressiveness and patient outcome. Methods We assayed in vitro the tumoral invasiveness and multidrug resistance in human lung adenocarcinoma (AdC) cell lines (EKVX and A549). Data were associated with several redox parameters and differential expression levels of HAG network. The clinicopathological significance of these findings was investigated using microarray analysis of tumor tissue and by immunohistochemistry in archival collection of biopsies. Results An overall increased activity (expression) of selected HAG components in the most aggressive cell line (EKVX cells) was observed by bootstrap and gene set enrichment analysis (GSEA). In vitro validation of oxidative markers revealed that EKVX cells had high levels of oxidative stress markers. In AdC cohorts, GSEA of microarray datasets showed significantly high levels of HAG components in lung AdC samples in comparison with normal tissue, in advanced stage compared with early stage and in patients with poor outcome. Cox multivariate regression analysis in a cohort of early pathologic (p)-stage of AdC cases showed that patients with moderate levels of 4-hydroxynonenal, a specific and stable end product of lipid peroxidation, had a significantly less survival rate (hazard ratio of 8.87) (P < 0.05). Conclusions High levels of oxidative markers are related to tumor aggressiveness and can predict poor outcome of early-stage lung adenocarcinoma patients. |
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