Suppression of IFN-induced transcription underlies IFN defects generated by activated Ras/MEK in human cancer cells.
Suppression of IFN-induced transcription underlies IFN defects generated by activated Ras/MEK in human cancer cells.
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DOI：
10.1371/journal.pone.0044267
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hirasawa K
中科院分区：
文献类型：
--
作者：
Christian SL;Zu D;Licursi M;Komatsu Y;Pongnopparat T;Codner DA;Hirasawa K
某些溶瘤病毒利用激活的RAS信号在癌细胞中复制。RAS/MEK途径的结构性激活被认为可以抑制干扰素(IFN)抗病毒反应的有效性，这可能有助于RAS依赖的病毒溶瘤。在这里，我们确定了10个人类癌细胞株(16个细胞株中)在用α抑制剂U0126处理后对干扰素-MEK的抗病毒作用增加了敏感性，这表明RAS/MEK途径是它们对干扰素敏感性降低的基础。为了确定RAS/MEK如何抑制这些细胞中的干扰素反应，我们使用DNA微阵列比较了干扰素敏感的SKOV3细胞、中度耐药的HT1080细胞和U0126处理的HT1080细胞中干扰素诱导的转录。我们发现，在同一时间点，干扰素在SKOV3细胞中诱导了267个基因的表达，而在HT1080细胞中只诱导了98个基因。U0126和干扰素联合作用后，HT1080细胞中RIGI、GBP2、IFIT2、BTN3A3、MAP2、MMP7和STAT2等干扰素诱导基因的表达恢复或增加。对这些基因所代表的生物过程的生物信息学分析表明，参与抗病毒反应、细胞凋亡调控、细胞分化和新陈代谢的基因表达增加。此外，在对干扰素敏感的SKOV3细胞中引入具有结构性活性的RAS，降低了它们对干扰素的敏感性和激活干扰素诱导转录的能力。这项工作首次证明，人类癌细胞中激活的RAS/MEK诱导干扰素诱导基因的特定子集下调。
Certain oncolytic viruses exploit activated Ras signaling in order to replicate in cancer cells. Constitutive activation of the Ras/MEK pathway is known to suppress the effectiveness of the interferon (IFN) antiviral response, which may contribute to Ras-dependent viral oncolysis. Here, we identified 10 human cancer cell lines (out of 16) with increased sensitivity to the anti-viral effects of IFN-α after treatment with the MEK inhibitor U0126, suggesting that the Ras/MEK pathway underlies their reduced sensitivity to IFN. To determine how Ras/MEK suppresses the IFN response in these cells, we used DNA microarrays to compare IFN-induced transcription in IFN-sensitive SKOV3 cells, moderately resistant HT1080 cells, and HT1080 cells treated with U0126. We found that 267 genes were induced by IFN in SKOV3 cells, while only 98 genes were induced in HT1080 cells at the same time point. Furthermore, the expression of a distinct subset of IFN inducible genes, that included RIGI, GBP2, IFIT2, BTN3A3, MAP2, MMP7 and STAT2, was restored or increased in HT1080 cells when the cells were co-treated with U0126 and IFN. Bioinformatic analysis of the biological processes represented by these genes revealed increased representation of genes involved in the anti-viral response, regulation of apoptosis, cell differentiation and metabolism. Furthermore, introduction of constitutively active Ras into IFN sensitive SKOV3 cells reduced their IFN sensitivity and ability to activate IFN-induced transcription. This work demonstrates for the first time that activated Ras/MEK in human cancer cells induces downregulation of a specific subset of IFN-inducible genes.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
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影响因子：
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影响因子：
5.4
作者：
Balachandran, S;Porosnicu, M;Barber, GN
通讯作者：
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