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.
J Cancer Res Clin Oncol. 2014 Mar;140(3):461-70. doi: 10.1007/s00432-014-1586-6. Epub 2014 Jan 22.
The expression levels of human antioxidant genes (HAGs) and oxidative markers were investigated in light of lung adenocarcinoma aggressiveness and patient outcome.
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.
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).
High levels of oxidative markers are related to tumor aggressiveness and can predict poor outcome of early-stage lung adenocarcinoma patients.
研究人类抗氧化基因（HAG）的表达水平和氧化标志物与肺腺癌侵袭性和患者预后的关系。
我们检测了体外人肺腺癌细胞系（EKVX 和 A549）的侵袭性和多药耐药性。数据与几个氧化还原参数和 HAG 网络的差异表达水平相关联。使用肿瘤组织的微阵列分析和活检存档集的免疫组织化学来研究这些发现的临床病理意义。
通过自举和基因集富集分析（GSEA）观察到最具侵袭性的细胞系（EKVX 细胞）中选定的 HAG 成分的整体活性（表达）增加。对氧化标志物的体外验证表明，EKVX 细胞具有高水平的氧化应激标志物。在肺腺癌队列中，微阵列数据集的 GSEA 显示，与正常组织相比，肺腺癌样本中的 HAG 成分水平明显较高，与早期阶段相比，晚期阶段水平较高，与预后不良的患者相比水平较高。在早期病理（p）期肺腺癌病例的队列中进行的 Cox 多变量回归分析表明，中等水平的 4-羟基壬烯醛（一种特定且稳定的脂质过氧化终产物）的患者的生存率明显较低（危险比为 8.87）（P<0.05）。
高水平的氧化标志物与肿瘤侵袭性有关，并可预测早期肺腺癌患者的不良预后。
