Division of Biomedical Science, Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada.
PLoS One. 2012;7(9):e44267. doi: 10.1371/journal.pone.0044267. Epub 2012 Sep 7.
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.
某些溶瘤病毒利用激活的 Ras 信号来在癌细胞中复制。已知 Ras/MEK 途径的组成性激活会抑制干扰素 (IFN) 的抗病毒反应的有效性，这可能有助于 Ras 依赖性病毒溶瘤作用。在这里，我们鉴定出 16 个人类癌细胞系中的 10 种（占 10 种）在用 MEK 抑制剂 U0126 处理后对 IFN-α 的抗病毒作用更敏感，这表明 Ras/MEK 途径是它们对 IFN 敏感性降低的基础。为了确定 Ras/MEK 如何在这些细胞中抑制 IFN 反应，我们使用 DNA 微阵列比较了 IFN 敏感的 SKOV3 细胞、中度耐药的 HT1080 细胞和用 U0126 处理的 HT1080 细胞中 IFN 诱导的转录。我们发现，267 个基因在 SKOV3 细胞中被 IFN 诱导，而在相同时间点，只有 98 个基因在 HT1080 细胞中被诱导。此外，当 HT1080 细胞与 U0126 和 IFN 共同处理时，一组独特的 IFN 诱导基因的表达被恢复或增加，包括 RIGI、GBP2、IFIT2、BTN3A3、MAP2、MMP7 和 STAT2。这些基因所代表的生物过程的生物信息学分析显示，抗病毒反应、细胞凋亡、细胞分化和代谢相关基因的表达增加。此外，将组成性激活的 Ras 引入 IFN 敏感的 SKOV3 细胞会降低其 IFN 敏感性和激活 IFN 诱导转录的能力。这项工作首次证明，人类癌细胞中的激活 Ras/MEK 诱导了一组特定的 IFN 诱导基因的下调。
