Imbalance in redox status is associated with tumor aggressiveness and poor outcome in lung adenocarcinoma patients.
OBJECTIVE
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.
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.
Leonardo
L
Lisbôa da Motta
Carolina B
CB
Müller
Marco A
MA
De Bastiani
Guilherme A
GA
Behr
Fernanda S
FS
França
Ricardo F
RF
da Rocha
Juliane B
JB
Minotto
Rosalva T
RT
Meurer
Marilda C
MC
Fernandes
Adriana
A
Roehe
Melissa M
MM
Markoski
Cristiano F
CF
Andrade
Mauro A A
MA
Castro
Fábio
F
Klamt
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000447:Aldehydes / Q000378:metabolism*; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016017:Odds Ratio; D010084:Oxidation-Reduction; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies
D000447:Aldehydes; D000975:Antioxidants; C027576:4-hydroxy-2-nonenal