Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, PR China.
Cancer Res. 2012 Apr 1;72(7):1890-900. doi: 10.1158/0008-5472.CAN-11-3472. Epub 2012 Feb 20.
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 patients with NPC. 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.
鼻咽癌（NPC）是一种与 Epstein-Barr 病毒相关的恶性肿瘤，在东亚和非洲最为常见。细胞周期抑制剂 p27 的负调控因子 Jab1/CSN5 的异常表达与 p27 表达降低相关，并与多种人类癌症的晚期肿瘤分期和不良预后相关。在本研究中，我们研究了 Jab1 和 p27 蛋白在 NPC 中的功能关系。免疫组化分析显示 NPC 组织样本中 Jab1 与 p27 呈负相关，并且 Jab1 过表达与 NPC 患者的不良预后相关。从机制上讲，在 NPC 细胞中发现 Jab1 和 p27 直接相互作用，Jab1 介导 p27 以蛋白酶体依赖的方式降解。Jab1 的敲低导致 p27 水平显著增加并抑制细胞增殖，表明 Jab1 将 p27 作为降解目标，从而控制其稳定性。Jab1 耗竭还增强了 NPC 细胞中顺铂的抗肿瘤作用。总之，我们的研究结果表明，Jab1 过表达通过 Jab1 介导的 p27 降解在 NPC 的发病机制中起重要作用。因此，Jab1 代表 NPC 患者的新型诊断标志物和治疗靶点。
