Sun Suna, Frontini Francesca, Qi Weihong, Hariharan Ananya, Ronner Manuel, Wipplinger Martin, Blanquart Christophe, Rehrauer Hubert, Fonteneau Jean-François, Felley-Bosco Emanuela
Laboratory of Molecular Oncology, Department of Thoracic Surgery, Lungen- und Thoraxonkologie Zentrum, University Hospital Zurich, Sternwartstrasse 14, 8091, Zurich, Switzerland.
Functional Genomics Center Zürich, ETH Zürich/University of Zürich, Zürich, Switzerland.
Cancer Lett. 2021 Jun 1;507:26-38. doi: 10.1016/j.canlet.2021.03.004. Epub 2021 Mar 10.
Early events in an experimental model of mesothelioma development include increased levels of editing in double-stranded RNA (dsRNA). We hypothesised that expression of endogenous retroviruses (ERV) contributes to dsRNA formation and type-I interferon signaling. ERV and interferon stimulated genes (ISGs) expression were significantly higher in tumor compared to non-tumor samples. 12 tumor specific ERV ("MesoERV1-12") were identified and verified by qPCR in mouse tissues. "MesoERV1-12" expression was lower in mouse embryonic fibroblasts (MEF) compared to mesothelioma cells. "MesoERV1-12" levels were significantly increased by demethylating agent 5-Aza-2'-deoxycytidine treatment and were accompanied by increased levels of dsRNA and ISGs. Basal ISGs expression was higher in mesothelioma cells compared to MEF and was significantly decreased by JAK inhibitor Ruxolitinib, by blocking Ifnar1 and by silencing Mavs. "MesoERV7" promoter was demethylated in asbestos-exposed compared to sham mice tissue as well as in mesothelioma cells and MEF upon 5-Aza-CdR treatment. These observations uncover novel aspects of asbestos-induced mesothelioma whereby ERV expression increases due to promoter demethylation and is paralleled by increased levels of dsRNA and activation of type-I IFN signaling. These features are important for early diagnosis and therapy.
间皮瘤发生实验模型中的早期事件包括双链RNA（dsRNA）编辑水平升高。我们假设内源性逆转录病毒（ERV）的表达有助于dsRNA的形成和I型干扰素信号传导。与非肿瘤样本相比，肿瘤中ERV和干扰素刺激基因（ISG）的表达显著更高。在小鼠组织中通过qPCR鉴定并验证了12种肿瘤特异性ERV（“MesoERV1 - 12”）。与间皮瘤细胞相比，小鼠胚胎成纤维细胞（MEF）中“MesoERV1 - 12”的表达较低。用去甲基化剂5 - 氮杂 - 2'-脱氧胞苷处理后，“MesoERV1 - 12”水平显著增加，并伴有dsRNA和ISG水平的升高。与MEF相比，间皮瘤细胞中基础ISG的表达更高，并且通过JAK抑制剂鲁索替尼、阻断Ifnar1和沉默Mavs可使其显著降低。与假手术小鼠组织相比，在石棉暴露小鼠组织中以及在5 - 氮杂 - 2'-脱氧胞苷处理后的间皮瘤细胞和MEF中，“MesoERV7”启动子去甲基化。这些观察结果揭示了石棉诱导的间皮瘤的新方面，即ERV表达因启动子去甲基化而增加，同时伴有dsRNA水平升高和I型干扰素信号激活。这些特征对早期诊断和治疗很重要。
