Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma
Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma
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DOI：
10.1007/s00428-014-1584-8
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发表时间：
2014-07-01
期刊：
影响因子：
3.5
通讯作者：
Popper, Helmut H.
中科院分区：
文献类型：
--
作者：
Arzt, Lisa;Kothmaier, Hannelore;Popper, Helmut H.
恶性胸膜间皮瘤（MPM）是最常见的胸膜原发性肿瘤。其发病率在欧洲不断增加，预后仍然很差。我们比较了上皮样MPM在短期和长期的幸存者，并确定信号转导和转录激活因子1（STAT 1）可能是负责抗凋亡信号和化疗耐药性。通过蛋白质印迹法评价六种间皮瘤细胞系。我们还分析了16例上皮样MPM组织样本的STAT 1磷酸化状态及其负调节因子细胞因子信号转导抑制因子1（SOCS 1）的表达。福尔马林固定和石蜡包埋的组织标本进行了评估，蛋白质裂解物芯片和免疫组化。我们发现STAT 1在MPM细胞系中高表达，STAT 3下调。干扰素-γ（IFN-γ）处理增加了酪氨酸701（Y 701）上磷酸化的STAT 1的表达，而SOCS 1不表达。在间皮瘤细胞系中未检测到丝氨酸727（S727）上磷酸化的STAT 1的表达，并且不受IFN-γ刺激。在MPM组织样本中，STAT 1在酪氨酸701和丝氨酸727上磷酸化。与pSTAT 1-S727相比，pSTAT 1-Y 701的表达增加。SOCS 1再次检测不到。STAT 1在MPM中上调，其作用可能因负调节剂SOCS 1的丧失而延长。因此，STAT 1可能是治疗干预的靶点，目的是恢复凋亡机制和对化疗的敏感性。然而，其他的调节机制需要进行调查，以澄清是否缺乏SOCS 1的表达是持续的STAT 1在MPM表达的唯一原因。
Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is increasing in Europe and the prognosis remains poor. We compared epithelioid MPM in short and long survivors, and identified signal transducer and activator of transcription 1 (STAT1) as probably being responsible for antiapoptotic signaling and chemoresistance. Six mesothelioma cell lines were evaluated by Western Blot. We also analyzed 16 epithelioid MPM tissue samples for the phosphorylation status of STAT1 and the expression of its negative regulator, the suppressor of cytokine signaling 1 (SOCS1). Formalin-fixed and paraffin-embedded tissue specimens were evaluated by protein-lysate microarray and immunohistochemistry. We found STAT1 to be highly expressed and STAT3 downregulated in MPM cell lines. The expression of STAT1 phosphorylated on tyrosine 701 (Y701) was increased by interferon-gamma (IFN-gamma) treatment, whereas SOCS1 was not expressed. The expression of STAT1 phosphorylated on serine 727 (S727) was not detected in mesothelioma cell lines and was not stimulated by IFN-gamma. STAT1 was phosphorylated on tyrosine 701 and serine 727 in MPM tissue samples. The expression of pSTAT1-Y701 was increased compared to pSTAT1-S727. SOCS1 was again not detectable. STAT1 is upregulated in MPM, and its action may be prolonged by a loss of the negative regulator SOCS1. STAT1 might, therefore, be a target for therapeutic intervention, with the intention to restore apoptotic mechanisms and sensitivity to chemotherapy. However, other regulatory mechanisms need to be investigated to clarify if lack of expression of SOCS1 is the only reason for sustained STAT1 expression in MPM.