Activation of the ERK1/2 Molecular Pathways and Its Relation to the Pathogenicity of Human Malignant Tumors.

IF 2 4区 生物学 Q4 CELL BIOLOGY
A G Emelyanova, M A Zolotovskaia, E V Poddubskaya, A A Modestov, V S Prassolov, D V Kuzmin, A A Buzdin
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Abstract

Mitogen-activated protein kinases, ERK1/2 (MAPK3/1), play a key role in the regulation of cell growth, differentiation, and apoptosis. We have previously presented evidence proving that activation of the ERK1/2 axis in cancer cells following the administration of therapeutics leads to the overexpression of growth factor receptors and drug resistance. Recently, we have proposed a new bioinformatic technique that enables direct construction of interactome network-based molecular pathways for gene products of interest, as well as quantitation of their activation levels using high-throughput gene expression data. In this study, we, for the first time, algorithmically constructed ERK1/2 molecular pathways and investigated how their activation levels (PALs) affect survival and responsiveness to targeted drugs at the pan-cancer level based on transcriptomic data. We examined a total of 11 287 human tumor profiles from 31 types of cancer, drawn from 53 of our previously published and other literature datasets, looking at patient survival and clinical response to 29 chemo- and targeted therapy regimens. We found that activation of the ERK1/2 pathways has different prognostic significance depending on cancer type. In glioblastoma, sarcoma, lung, kidney, bladder, gastric, colon, and several other cancer types, ERK pathway activation was associated with worse survival. In contrast, the same phenomenon was associated with a better chance of survival in HER2+, luminal A and luminal B breast cancer, and uterine corpus cancer. These trends were consistent with treatment response analysis. At the same time, we found significantly worse associations with the expression levels of individual MAPK1 and MAPK3 genes: hence, ERK1/2 pathway activation levels can be considered putative biomarkers for predicting clinical outcomes and selecting new personalized treatment strategies, such as the use of MAPK inhibitors.

ERK1/2分子通路的激活及其与人类恶性肿瘤致病性的关系
丝裂原活化蛋白激酶ERK1/2 (MAPK3/1)在细胞生长、分化和凋亡的调控中发挥关键作用。我们之前提出的证据证明,在接受治疗后,癌细胞中ERK1/2轴的激活会导致生长因子受体的过度表达和耐药性。最近,我们提出了一种新的生物信息学技术,可以直接构建基于相互作用组网络的基因产物分子通路,并使用高通量基因表达数据定量其激活水平。在这项研究中,我们首次基于转录组学数据,算法构建了ERK1/2分子通路,并研究了它们的激活水平(PALs)如何影响泛癌症水平的生存和对靶向药物的反应性。我们检查了来自31种癌症的11 287例人类肿瘤谱,这些数据来自我们之前发表的53个文献数据集和其他文献数据集,研究了患者对29种化疗和靶向治疗方案的生存和临床反应。我们发现ERK1/2通路的激活根据癌症类型具有不同的预后意义。在胶质母细胞瘤、肉瘤、肺癌、肾癌、膀胱癌、胃癌、结肠癌和其他几种癌症类型中,ERK通路激活与较差的生存率相关。相比之下,同样的现象与HER2+、腔内a和腔内B乳腺癌和子宫癌的更好的生存机会相关。这些趋势与治疗反应分析一致。同时,我们发现与个体MAPK1和MAPK3基因表达水平的相关性明显较差:因此,ERK1/2通路激活水平可以被认为是预测临床结果和选择新的个性化治疗策略(如使用MAPK抑制剂)的推定生物标志物。
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来源期刊
Acta Naturae
Acta Naturae 农林科学-林学
CiteScore
3.50
自引率
5.00%
发文量
0
审稿时长
>12 weeks
期刊介绍: Acta Naturae is an international journal on life sciences based in Moscow, Russia. Our goal is to present scientific work and discovery in molecular biology, biochemistry, biomedical disciplines and biotechnology. These fields represent the most important priorities for the research and engineering development both in Russia and worldwide. Acta Naturae is also a periodical for those who are curious in various aspects of biotechnological business, innovations in pharmaceutical areas, intellectual property protection and social consequences of scientific progress. The journal publishes analytical industrial surveys focused on the development of different spheres of modern life science and technology. Being a radically new and totally unique journal in Russia, Acta Naturae is useful to both representatives of fundamental research and experts in applied sciences.
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