Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia.
Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia.
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DOI：
10.18632/oncotarget.24808
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发表时间：
2018-04-13
期刊：
影响因子：
--
通讯作者：
Lundberg E
中科院分区：
文献类型：
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作者：
Danielsson F;Fasterius E;Sullivan D;Hases L;Sanli K;Zhang C;Mardinoglu A;Al-Khalili C;Huss M;Uhlén M;Williams C;Lundberg E
在肿瘤组织中，缺氧是一种常见的特征，这是由于癌细胞快速增殖超出其周围的脉管系统网络而导致的。众所周知，转化的癌细胞会表现出表型改变，尽管氧气供应有限，但仍能持续增殖。四步同基因 BJ 细胞模型能够研究肿瘤发生的定义步骤：正常、永生化、转化和转移阶段。通过大气和中度缺氧（3% O2）条件下的转录组分析，我们观察到，尽管 BJ 模型的四种细胞系高度相似，但它们对缺氧的反应却截然不同。除了证实许多已知的缺氧反应外，我们还证明转录组对中度缺氧的适应类似于恶性转化的过程。转化的细胞表现出独特的代谢转换能力，这反映在参与氧化磷酸化和糖酵解途径的几个基因的反向基因表达模式上。通过分析对缺氧的阶段特异性反应，我们将 ASS1 确定为缺氧肿瘤的潜在预后标志物。这项研究证明了 BJ 细胞模型在强调恶性转化和缺氧反应相关途径的相互联系方面的有用性。
In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing their surrounding vasculature network. Transformed cancer cells are known to exhibit phenotypic alterations, enabling continuous proliferation despite a limited oxygen supply. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines of the BJ model responded strikingly different to hypoxia. Besides corroborating many of the known responses to hypoxia, we demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.