STAT3-iNOS Signaling Mediates EGFRvIII-Induced Glial Proliferation and Transformation.
STAT3-iNOS Signaling Mediates EGFRvIII-Induced Glial Proliferation and Transformation.
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DOI：
10.1523/jneurosci.3243-11.2012
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发表时间：
2012-06-06
期刊：
影响因子：
--
通讯作者：
Bonni A
中科院分区：
文献类型：
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作者：
Puram SV;Yeung CM;Jahani-Asl A;Lin C;de la Iglesia N;Konopka G;Jackson-Grusby L;Bonni A
恶性胶质瘤，包括多形性胶质母细胞瘤，构成成人中最常见和最具侵袭性的原发性脑肿瘤。转录因子信号转导子和转录激活子 3 (STAT3) 在主要致癌蛋白表皮生长因子受体变体 III (EGFRvIII) 下游的胶质母细胞瘤发病机制中发挥重要作用。然而，STAT3 介导 EGFRvIII 诱导的神经胶质细胞转化的关键基因靶点仍不清楚。在这里，我们将诱导型一氧化氮合酶（iNOS）确定为表达 EGFRvIII 的小鼠星形胶质细胞中 STAT3 的新靶基因。内源性 STAT3 占据内源性 iNOS 启动子并刺激表达 EGFRvIII 的星形胶质细胞中的 iNOS 转录。 STAT3似乎不控制缺乏主要胶质母细胞瘤肿瘤抑制蛋白PTEN的星形胶质细胞中的iNOS转录，这表明STAT3特异性地在表达EGFRvIII的星形胶质细胞中调节iNOS转录。重要的是，通过不同的方法抑制 iNOS，包括通过 RNA 干扰敲低，可减少细胞群生长和表达 EGFRvIII 的星形胶质细胞的侵袭性。此外，在 iNOS 敲低或给予 iNOS 小分子抑制剂后，表达 EGFRvIII 的星形胶质细胞在体内形成更小的肿瘤。这些发现表明，iNOS 的抑制可能对 EGFRvIII 激活的脑肿瘤具有潜在的治疗价值。
Malignant gliomas, including glioblastoma multiforme, constitute the most common and aggressive primary brain tumors in adults. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays an essential role in glioblastoma pathogenesis downstream of the major oncogenic protein epidermal growth factor receptor variant III (EGFRvIII). However, the critical gene targets of STAT3 that mediate EGFRvIII-induced glial transformation have remained unknown. Here, we identify inducible nitric oxide synthase (iNOS) as a novel target gene of STAT3 in EGFRvIII-expressing mouse astrocytes. Endogenous STAT3 occupies the endogenous iNOS promoter and stimulates iNOS transcription in EGFRvIII-expressing astrocytes. STAT3 does not appear to control iNOS transcription in astrocytes deficient in the major glioblastoma tumor suppressor protein PTEN, suggesting that STAT3 regulates iNOS transcription specifically in EGFRvIII-expressing astrocytes. Importantly, inhibition of iNOS by distinct approaches including knockdown by RNA interference reduces cell population growth and invasiveness of EGFRvIII-expressing astrocytes. In addition, upon iNOS knockdown or administration of a small molecule inhibitor of iNOS, EGFRvIII-expressing astrocytes form smaller tumors in vivo. These findings suggest that inhibition of iNOS may have potential therapeutic value for EGFRvIII-activated brain tumors.