Differential signaling pathways are activated in the Epstein-Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma
Differential signaling pathways are activated in the Epstein-Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma
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DOI：
10.1158/0008-5472.can-04-0538
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Raab-Traub, N
中科院分区：
文献类型：
--
作者：
Morrison, JA;Gulley, ML;Raab-Traub, N
EB病毒与上皮性癌、鼻咽癌(NPC)和淋巴系统恶性肿瘤霍奇金淋巴瘤(HL)有关。EBV潜伏膜蛋白1和2 A在这些肿瘤中表达。这些蛋白激活磷脂酰肌醇3‘-羟基激酶(PI3K)/Akt通路，该通路在恶性肿瘤中通常被不适当地激活。本研究对鼻咽癌和HL临床标本中Akt的激活状态及其靶点--糖原合成酶-3β(GSK-3β)和β-连环蛋白进行了研究。在大多数HL和NPC标本中，Akt被激活，这表明该激酶在这些肿瘤的发生和/或进展中起着重要作用。AKT使GSK-3β磷酸化并失活，GSK-3β是原癌蛋白β-连环素的负调控因子，在许多癌症中被异常激活。在大多数鼻咽癌标本中，GSK-3β被磷酸化并失活，并伴随着核β-连环蛋白的积聚。然而，大多数HL患者的恶性细胞没有失活的GSK-3β，并且缺乏核β-连环蛋白的表达。这些数据表明，PI3K/Akt的这一信号臂在鼻咽癌的发病机制中具有普遍性和重要性，但在HL中显然不受影响。这些发现表明，在不同的细胞环境中，EBV激活的通路存在差异。
EBV is associated with the epithelial cancer, nasopharyngeal carcinoma (NPC), and the lymphoid malignancy, Hodgkin lymphoma (HL). The EBV latent membrane proteins 1 and 2A are expressed in these tumors. These proteins activate the phosphatidylinositol 3'-OH kinase (PI3K)/Akt pathway, which is commonly activated inappropriately in malignancy. In this study, the status of Akt activation and its targets, glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin, was investigated in NPC and HL clinical specimens. In the majority of HL and NPC specimens, Akt was activated, indicating an important role for this kinase in the development and/or progression of these tumors. Akt phosphorylates and inactivates GSK-3beta, a negative regulator of the proto-oncoprotein beta-catenin that is aberrantly activated in many cancers. GSK-3beta was phosphorylated and inactivated with concomitant nuclear beta-catenin accumulation in the majority of NPC specimens. The malignant cells of the majority of HL cases, however, did not have inactivated GSK-3beta and lacked nuclear beta-catenin expression. These data indicate that this signaling arm of PI3K/Akt is universal and important in NPC pathogenesis but is apparently not affected in HL. These findings point to a divergence in pathways activated by EBV in different cellular contexts.