Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene. 2013 May 30;32(22):2756-66. doi: 10.1038/onc.2012.294. Epub 2012 Jul 16.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin. Increased DNA damage repair is one of the mechanisms contributing to this resistance. Jab1/CSN5 is a multifunctional protein that participates in controlling cell proliferation and the stability of multiple proteins. Jab1 overexpression has been found to correlate with poor prognosis in several tumor types. However, the biological significance of Jab1 activity in response to cancer treatment is unclear. In this study, we used three NPC cell lines (CNE1, CNE2 and HONE1) to investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, cellular response to treatment with DNA-damaging agents such as cisplatin, ionizing radiation (IR) and ultraviolet (UV) radiation. We found that Jab1 was overexpressed in two relatively cisplatin-, IR- and UV-resistant NPC cell lines, and knocking down its expression conferred sensitivity to cisplatin, IR and UV radiation. By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV radiation. Moreover, we provide a mechanism by which Jab1 positively regulated Rad51 through p53-dependent pathway, and increased ectopic expression of Rad51 conferred cellular resistance to cisplatin, IR and UV radiation in Jab1-deficient cells. Taken together, our findings suggest that Jab1 has an important role in the cellular response to cisplatin and irradiation by regulating DNA damage and repair pathways. Therefore, Jab1 is a novel biomarker for predicting the outcome of patients with NPC who are treated with DNA-damaging agents.
鼻咽癌（NPC）是一种 Epstein-Barr 病毒相关的恶性肿瘤，在东亚和非洲最为常见。放射治疗和顺铂为基础的化疗是主要的治疗选择。不幸的是，NPC 患者对同期放化疗的反应存在差异，许多病例对顺铂耐药。增加的 DNA 损伤修复是导致这种耐药性的机制之一。Jab1/CSN5 是一种多功能蛋白，参与控制细胞增殖和多种蛋白质的稳定性。Jab1 的过表达已被发现与几种肿瘤类型的不良预后相关。然而，Jab1 活性在癌症治疗中的生物学意义尚不清楚。在这项研究中，我们使用三种 NPC 细胞系（CNE1、CNE2 和 HONE1）来验证 Jab1 是否正向调节 DNA 修复蛋白 Rad51，进而影响 NPC 细胞对顺铂、电离辐射（IR）和紫外线（UV）等 DNA 损伤剂的治疗反应的假设。我们发现 Jab1 在两种相对耐顺铂、IR 和 UV 的 NPC 细胞系中过表达，敲低其表达可使 NPC 细胞对顺铂、IR 和 UV 辐射敏感。相比之下，外源性 Jab1 表达增强了 NPC 细胞对顺铂、IR 和 UV 辐射的耐药性。此外，我们提供了一种机制，即 Jab1 通过 p53 依赖性途径正向调节 Rad51，并增加 NPC 细胞中 Rad51 的异位表达可赋予细胞对 Jab1 缺陷细胞中顺铂、IR 和 UV 辐射的耐药性。总之，我们的研究结果表明，Jab1 通过调节 DNA 损伤和修复途径在 NPC 细胞对顺铂和照射的反应中发挥重要作用。因此，Jab1 是预测接受 DNA 损伤剂治疗的 NPC 患者预后的新型生物标志物。
