Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers.
Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers.
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DOI：
10.18632/oncotarget.1658
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Knight RA
中科院分区：
文献类型：
--
作者：
Rotblat B;Grunewald TG;Leprivier G;Melino G;Knight RA
细胞启动转录抗氧化应激（AOS）反应程序，以抑制化学、物理和代谢挑战产生的活性氧（ROS）。这种保护性程序已被证明可以减少化学和物理损伤引发的致癌作用。然而，它也被已建立的癌症劫持，在敌对的肿瘤微环境中茁壮成长和增殖，并获得对化疗和放疗的抵抗力。因此，靶向被癌细胞利用的AOS应答蛋白是一种有吸引力的治疗策略。为了鉴定被怀疑支持癌症进展和抗性的AOS基因，我们分析了994个肿瘤和353个正常组织中285个注释为参与氧化应激的基因的表达模式。因此，我们确定了116个基因的特征，这些基因在多种癌症中高度过表达，而在正常组织中仅极低表达。为了确定这些基因中哪些更有可能在功能上驱动癌症耐药性和进展，我们进一步鉴定了那些过表达与乳腺癌和肺癌患者阴性结局相关的基因。基因集富集、基因本体、网络和途径分析揭示，硫氧还蛋白和谷胱甘肽途径的成员是这种致癌特征的突出组分，并且这些途径的激活是许多癌症实体的共同特征。有趣的是，这些AOS基因中的大部分是转录因子NRF 2、NF-κ B和FOXM 1的下游靶标，并且依赖于NADPH的酶活性，突出了有希望的药物靶标。我们讨论了这些发现，并提出了可能适用于克服癌症耐药性的治疗策略。
Cells mount a transcriptional anti-oxidative stress (AOS) response program to scavenge reactive oxygen species (ROS) that arise from chemical, physical, and metabolic challenges. This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults. However, it is also hijacked by established cancers to thrive and proliferate within the hostile tumor microenvironment and to gain resistance against chemo- and radiotherapies. Therefore, targeting the AOS response proteins that are exploited by cancer cells is an attractive therapeutic strategy. In order to identify the AOS genes that are suspected to support cancer progression and resistance, we analyzed the expression patterns of 285 genes annotated for being involved in oxidative stress in 994 tumors and 353 normal tissues. Thereby we identified a signature of 116 genes that are highly overexpressed in multiple cancers while being only minimally expressed in normal tissues. To establish which of these genes are more likely to functionally drive cancer resistance and progression, we further identified those whose overexpression correlates with negative patient outcome in breast and lung carcinoma. Gene-set enrichment, gene ontology, network, and pathway analyses revealed that members of the thioredoxin and glutathione pathways are prominent components of this oncogenic signature and that activation of these pathways is common feature of many cancer entities. Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB, and FOXM1, and rely on NADPH for their enzymatic activities highlighting promising drug targets. We discuss these findings and propose therapeutic strategies that may be applied to overcome cancer resistance.
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影响因子：
9
作者：
通讯作者：
--
影响因子：
11.2
作者：
Dai B;Yoo SY;Bartholomeusz G;Graham RA;Majidi M;Yan S;Meng J;Ji L;Coombes K;Minna JD;Fang B;Roth JA
通讯作者：
Roth JA
影响因子：
50.3
作者：
Anders L;Ke N;Hydbring P;Choi YJ;Widlund HR;Chick JM;Zhai H;Vidal M;Gygi SP;Braun P;Sicinski P
通讯作者：
Sicinski P
DOI：
10.1016/s0167-4781(00)00238-4
发表时间：
2000-12-15
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Chan, JY;Kwong, M
通讯作者：
Kwong, M
Profcom：用于分析从高通量数据识别的基因组复杂功能的Web工具。
影响因子：
14.9
作者：
Antonov, Alexey V.;Schmidt, Thorsten;Wang, Yu;Mewes, Hans W.
通讯作者：
Mewes, Hans W.