Functional annotation of IFN-α-stimulated gene expression profiles from sensitive and resistant renal cell carcinoma cell lines
Functional annotation of IFN-α-stimulated gene expression profiles from sensitive and resistant renal cell carcinoma cell lines
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DOI：
10.1089/jir.2006.26.534
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发表时间：
2006-08-01
影响因子：
2.3
通讯作者：
Williams, Bryan R. G.
中科院分区：
文献类型：
--
作者：
Holko, Michelle;Williams, Bryan R. G.
干扰素（IFN）的抗增殖、抗病毒和免疫调节特性已经导致其治疗实施。IFN的作用是由一个复杂的信号转导网络介导的，最终在IFN刺激基因（ISG）诱导。这种复杂性导致对IFN的不同临床反应，从无反应到疾病完全消退。因此，阐明ISG诱导模式对于理解和最大化其治疗潜力至关重要。为了将ISG表达谱与IFN反应性相关联，用IFN-α处理两种抗病毒和对IFN的凋亡反应不同的肾细胞癌（RCC）细胞系不同时间，并使用含有850个独特推定ISG的定制微阵列分析表达谱。对两种细胞系中具有相似诱导动力学的基因进行聚类并分析基因功能。通过k-means聚类分析确定了7组协同调控的基因，其中5组具有显著的功能相似性。引人注目的是，与转录相关的基因的表达暂时先于参与信号转导的基因的表达。增强的抗病毒敏感性IFN是一致的持续表达的ISGs参与转录调控。然而，在细胞系之间没有观察到Stat 1活化的差异。ISG表达模式的分析表明，转录谱的细微差异有助于IFN反应性的差异。
The antiproliferative, antiviral, and immunomodulatory properties of interferons (IFNs) have led to its therapeutic implementation. IFNs effects are mediated by a complex network of signal transducers, culminating in IFN-stimulated gene (ISG) induction. This complexity leads to diverse clinical responses to IFN, from no response to complete regression of disease. Elucidation of ISG induction patterns is, therefore, essential to understand and maximize its therapeutic potential. To correlate ISG expression profiles with IFN responsiveness, two renal cell carcinoma (RCC) cell lines differing in antiviral and apoptotic response to IFN were treated with IFN-alpha for different times, and expression profiles were analyzed using a customized microarray containing 850 unique putative ISGs. Genes with similar kinetics of induction in both cell lines were clustered and analyzed for gene function. Seven sets of coordinately regulated genes were identified by k-means cluster analysis, and significant functional similarities were identified for five of the seven sets. Strikingly, expression of genes associated with transcription temporally preceded expression of those involved in signal transduction. Enhanced antiviral sensitivity to IFN was coincident with sustained expression of ISGs involved in transcriptional regulation. However, no difference in Stat1 activation was observed between the cell lines. Analysis of ISG expression patterns suggests that subtle differences in transcription profiles contribute to differences in IFN responsiveness.