Clinical Institute of Pathology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1097, Austria.
Cancer. 2011 Jun 1;117(11):2499-504. doi: 10.1002/cncr.25799. Epub 2010 Dec 14.
Animal studies have shown cooperative contribution of the Ras/Raf/MAPK and PI3K/Akt/mTOR signaling pathways in glioblastoma formation. However, this joint action has not yet been confirmed in human studies.
The expression of Raf kinase inhibitory protein (RKIP) was examined in 159 patients with high-grade and low-grade gliomas and correlated with previously obtained data on the activation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the PI3K/Akt/mTOR signaling pathway.
RKIP expression was associated with a longer overall survival in high-grade glioma cases without showing a direct or inverse correlation with tyrosine-705 phosphorylation of STAT3 (pSTAT3). Notably, RKIP-positive and pSTAT3 negative cases demarcate a patients group with exceptionally long survival, exceeding the prognostic impact of each single marker.
The results of this study indicated that 1) RKIP expression correlates with tumor grade and is a marker for good prognosis in high-grade gliomas; 2) RKIP expression and lack of pSTAT3 have a cumulative prognostic impact; and 3) RKIP and pSTAT3 are likely to operate independently to influence survival. These findings represented the first human evidence of an additive effect of 2 distinct signaling pathways in high-grade glioma, suggesting that simultaneous inhibition of multiple pathways should be considered as a treatment strategy for these patients.
动物研究表明，Ras/Raf/MAPK 和 PI3K/Akt/mTOR 信号通路在胶质母细胞瘤的形成中具有协同作用。然而，这种联合作用尚未在人类研究中得到证实。
研究人员检测了 159 名高级别和低级别胶质瘤患者中 Raf 激酶抑制蛋白（RKIP）的表达情况，并将其与之前获得的关于信号转导子和转录激活子 3（STAT3）激活的数据进行了关联，STAT3 是 PI3K/Akt/mTOR 信号通路的下游效应物。
RKIP 的表达与高级别胶质瘤患者的总生存期延长相关，与 STAT3 的酪氨酸-705 磷酸化（pSTAT3）没有直接或间接的相关性。值得注意的是，RKIP 阳性且 pSTAT3 阴性的病例划定了一个患者群体，其生存时间异常长，超过了每个单一标志物的预后影响。
这项研究的结果表明：1）RKIP 的表达与肿瘤分级相关，是高级别胶质瘤患者预后良好的标志物；2）RKIP 表达和缺乏 pSTAT3 具有累积的预后影响；3）RKIP 和 pSTAT3 可能独立运作以影响生存。这些发现代表了两种不同信号通路在高级别胶质瘤中具有累加效应的首例人类证据，表明同时抑制多个通路可能被认为是这些患者的一种治疗策略。
