Morrison Jennifer A, Gulley Margaret L, Pathmanathan Rajadurai, Raab-Traub Nancy
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Cancer Res. 2004 Aug 1;64(15):5251-60. doi: 10.1158/0008-5472.CAN-04-0538.
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.
EB病毒与上皮癌鼻咽癌（NPC）以及淋巴恶性肿瘤霍奇金淋巴瘤（HL）相关。EB病毒潜伏膜蛋白1和2A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信号通路，该通路在恶性肿瘤中通常被异常激活。在本研究中，在NPC和HL临床标本中研究了Akt激活状态及其靶点糖原合酶激酶-3β（GSK-3β）和β-连环蛋白的情况。在大多数HL和NPC标本中，Akt被激活，表明该激酶在这些肿瘤的发生和/或进展中起重要作用。Akt使GSK-3β磷酸化并使其失活，GSK-3β是原癌蛋白β-连环蛋白的负调节因子，在许多癌症中被异常激活。在大多数NPC标本中，GSK-3β被磷酸化并失活，同时伴有核β-连环蛋白积累。然而，大多数HL病例的恶性细胞中，GSK-3β未失活且缺乏核β-连环蛋白表达。这些数据表明PI3K/Akt的这条信号通路在NPC发病机制中普遍且重要，但在HL中显然未受影响。这些发现表明EB病毒在不同细胞环境中激活的信号通路存在差异。
