Magrassi L, De-Fraja C, Conti L, Butti G, Infuso L, Govoni S, Cattaneo E
Neurosurgery Department, Policlinico San Matteo, and Institute of Pharmacology, University of Pavia, Italy.
J Neurosurg. 1999 Sep;91(3):440-6. doi: 10.3171/jns.1999.91.3.0440.
The goal of this study was to investigate whether the janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction pathway is present and active in meningiomas. The results of these investigations are important for all meningioma therapies that, similar to interferon-alpha-2B (IFNalpha-2B), depend on activation of this pathway for their effect. The authors were interested in evaluating the importance, if any, of the JAK/STAT pathway in the biology and therapy for these tumors.
Total proteins were extracted from 17 meningioma samples and the levels of JAKs and STATs were determined by using Western blot analysis. Levels of these proteins in meningiomas were compared with those found in normal dura. The JAKs and STATs (with the exception of Jak3 and Tyk2) were present both in the dura and in the meningiomas studied. In tumors JAK and STAT levels were always significantly higher than those found in normal dura. Differences in relative levels were found when meningiomas were subdivided according to the current neuropathological criteria and the highest levels were found in transitional meningiomas. The authors also investigated, using tyrosine-phosphorylated Statl and Stat3 antibodies, whether STATs were activated in meningiomas and normal dura in vivo. Their results indicate that both Statl and Stat3 are phosphorylated in vivo in meningiomas and in the dura. Furthermore, in vitro experiments in which two independent short-term cultures obtained from freshly dissected meningioma samples were used indicated that Statl and Stat3 are phosphorylated in response to treatment with IFNalpha-2B. Exposure of meningioma cells to IFNalpha-2B leads to nuclear translocation of tyrosine-phosphorylated Statl and Stat3, as demonstrated by immunocytochemical analysis.
The results of this study indicate that the JAK and STAT families of proteins are important effectors in brain tumors and support the idea that the effects of IFNalpha in vivo are direct and not mediated by the immune system. This suggests a role for modulation of STAT transcription factors in inhibiting meningioma cell proliferation.
本研究的目的是调查在脑膜瘤中是否存在Janus激酶/信号转导及转录激活因子（JAK/STAT）信号转导通路并具有活性。这些研究结果对于所有与干扰素α-2B（IFNα-2B）类似、依赖该通路激活来发挥作用的脑膜瘤治疗方法而言都很重要。作者感兴趣的是评估JAK/STAT通路在这些肿瘤的生物学特性及治疗中的重要性（若存在重要性的话）。
从17例脑膜瘤样本中提取总蛋白，采用蛋白质免疫印迹分析测定JAK和STAT的水平。将脑膜瘤中这些蛋白的水平与正常硬脑膜中的水平进行比较。所研究的硬脑膜和脑膜瘤中均存在JAK和STAT（Jak3和Tyk2除外）。肿瘤中JAK和STAT的水平总是显著高于正常硬脑膜中的水平。根据当前神经病理学标准对脑膜瘤进行细分时，发现相对水平存在差异，其中过渡型脑膜瘤中的水平最高。作者还使用酪氨酸磷酸化的Stat1和Stat3抗体研究了STAT在脑膜瘤和正常硬脑膜中的体内激活情况。他们的结果表明，Stat1和Stat3在脑膜瘤和硬脑膜的体内均发生磷酸化。此外，使用从新鲜解剖的脑膜瘤样本中获得的两个独立短期培养物进行的体外实验表明，Stat1和Stat3在接受IFNα-2B治疗后发生磷酸化。免疫细胞化学分析表明，脑膜瘤细胞暴露于IFNα-2B会导致酪氨酸磷酸化的Stat1和Stat3发生核转位。
本研究结果表明，JAK和STAT蛋白家族是脑肿瘤中的重要效应分子，并支持IFNα在体内的作用是直接的而非由免疫系统介导这一观点。这表明STAT转录因子的调节在抑制脑膜瘤细胞增殖中具有作用。
