Jab1/CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma.
Jab1/CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma.
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DOI：
10.1158/0008-5472.can-11-3472
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Pan Y;Zhang Q;Tian L;Wang X;Fan X;Zhang H;Claret FX;Yang H
鼻咽癌（NPC）是一种EB病毒相关的恶性肿瘤，最常见于东亚和非洲。Jab 1/CSN 5是细胞周期抑制剂p27的负调控因子，其异常表达与p27表达减少相关，并与几种人类癌症的晚期肿瘤阶段和不良预后相关。在这项研究中，我们研究了Jab 1和p27蛋白表达在NPC中的功能关系。免疫组化分析显示Jab 1和p27在NPC组织样本中呈负相关，Jab 1的过度表达与NPC患者的生存率低相关。机制上，Jab 1和p27被发现直接在NPC细胞中相互作用，Jab 1以蛋白酶体依赖的方式介导p27降解。Jab 1的敲除导致p27水平显着增加并抑制细胞增殖，表明Jab 1靶向p27降解，从而控制其稳定性。Jab 1缺失也增强了顺铂在NPC细胞中的抗肿瘤作用。总之，我们的研究结果表明，Jab 1过表达通过Jab 1介导的p27降解在NPC的发病机制中起着重要作用。因此，Jab 1代表了NPC患者的新诊断标志物和治疗靶点。
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Aberrant expression of Jab1/CSN5, a negative regulator of the cell cycle inhibitor p27, is correlated with reduced p27 expression and associated with advanced tumor stage and poor prognosis in several human cancers. In this study, we examined the functional relationship between Jab1 and p27 protein expression in NPC. Immunohistochemical analysis showed an inverse association between Jab1 and p27 in NPC tissue samples, and overexpression of Jab1 correlated with poor survival in NPC patients. Mechanistically, Jab1 and p27 were found to interact directly in NPC cells, with Jab1 mediating p27 degradation in a proteasome-dependent manner. Knockdown of Jab1 resulted in a remarkable increase in p27 levels and inhibition of cell proliferation, indicating that Jab1 targets p27 for degradation, thereby controlling its stability. Jab1 depletion also enhanced the antitumor effects of cisplatin in NPC cells. Together, our findings suggest that Jab1 overexpression plays an important role in the pathogenesis of NPC through Jab1-mediated p27 degradation. Jab1 therefore represents a novel diagnostic marker and therapeutic target in patients with NPC.