Malignant mesothelioma (MM) constitutes a very aggressive tumor that is caused by asbestos exposure after long latency. The NF2 tumor suppressor gene is mutated in 40-50% of MM; moreover, one of its downstream signaling cascades, the Hippo signaling pathway, is also frequently inactivated in MM cells. Although the YAP transcriptional coactivator, which is regulated by the Hippo pathway, can function as a pro-oncogenic protein, the role of TAZ, a paralog of YAP, in MM cells has not yet been clarified. Here, we show that TAZ is expressed and underphosphorylated (activated) in the majority of MM cells compared to immortalized mesothelial cells. ShRNA-mediated TAZ knockdown highly suppressed cell proliferation, anchorage-independent growth, cell motility, and invasion in MM cells harboring activated TAZ. Conversely, transduction of an activated form of TAZ in immortalized mesothelial cells enhanced these in vitro phenotypes and conferred tumorigenicity in vivo. Microarray analysis determined that activated TAZ most significantly enhanced the transcription of genes related to "cytokine-cytokine receptor interaction." Among selected cytokines, we found that IL-1 signaling activation plays a major role in proliferation in TAZ-activated MM cells. Both IL1B knockdown and an IL-1 receptor antagonist significantly suppressed malignant phenotypes of immortalized mesothelial cells and MM cells with activated TAZ. Overall, these results indicate an oncogenic role for TAZ in MMs via transcriptional induction of distinct pro-oncogenic genes including cytokines. Among these, IL-1 signaling appears as one of the most important cascades, thus potentially serving as a target pathway in MM cells harboring Hippo pathway inactivation.

中文翻译：

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由河马途径失调引起的TAZ激活诱导细胞因子基因表达并促进间皮细胞转化。

恶性间皮瘤（MM）构成了一种非常具有侵略性的肿瘤，是由长时间潜伏的石棉暴露引起的。NF2肿瘤抑制基因在MM的40-50％中发生突变；此外，其下游信号传导级联之一，河马信号传导途径，在MM细胞中也经常失活。尽管受Hippo途径调节的YAP转录共激活因子可以起促癌蛋白的作用，但尚未阐明TAP在Y细胞中的作用，在MM细胞中尚不清楚。在这里，我们显示，与永生化的间皮细胞相比，TAZ在大多数MM细胞中表达和磷酸化不足（激活）。ShRNA介导的TAZ抑制可高度抑制细胞增殖，不依赖锚定的生长，细胞运动以及对带有活化TAZ的MM细胞的侵袭。反过来，在永生化的间皮细胞中转导活化形式的TAZ增强了这些体外表型并赋予了体内致瘤性。微阵列分析确定活化的TAZ最显着增强了与“细胞因子-细胞因子受体相互作用”有关的基因的转录。在选定的细胞因子中，我们发现IL-1信号激活在TAZ激活的MM细胞增殖中起主要作用。IL1B敲低和IL-1受体拮抗剂都可以显着抑制永生化的间皮细胞和具有活化TAZ的MM细胞的恶性表型。总体而言，这些结果表明TAZ在MM中的致癌作用是通过转录诱导的包括细胞因子在内的独特的致癌基因进行的。在这些信号中，IL-1信号似乎是最重要的级联之一，