Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR.
J Pathol. 2012 Feb;226(3):471-81. doi: 10.1002/path.2997. Epub 2011 Oct 19.
Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy which is prevalent in south-east Asia and southern China. Despite the multiple genetic and epigenetic changes reported, the contribution of dysregulated signalling pathways to this distinct type of head and neck cancer is not well understood. Here we demonstrate the up-regulation of NOTCH ligands (JAG1 or DLL4) and effector (HEY1) in the majority of EBV-positive tumour lines and primary tumours. Among the NOTCH receptors, NOTCH3 was over-expressed in all EBV-positive tumour lines and 92.5% of primary tumours. Aberrant activation of NOTCH3 signalling was consistently detected in all these samples. These findings imply that NOTCH3 may play an crucial role in the development of NPC. By NOTCH3 specific siRNA, NOTCH3 signalling was suppressed and thereby significant growth inhibition and apoptosis induction occurred in NPC cells. Down-regulation of a number of targets involved in cell proliferation, eg CCND1, C-MYC,NFKB1, and survival, eg BCL2, BCL-XL, SURVIVIN, was confirmed in the NOTCH3 knockdown NPC cells. Importantly, NOTCH3 knockdown highly enhanced the sensitivity of NPC cells to cisplatin treatment. Furthermore, we revealed that the ability of NPC cells to form spheroids in vitro and tumours in nude mice was also significantly decreased after knockdown of NICD3 expression. These findings indicate that activation of NOTCH3 pathway is a critical oncogenic event in NPC tumourigenesis. Targeting NOTCH3 signalling may serve as a potential therapeutic approach for treating patients suffering from EBV-associated NPC.
鼻咽癌（NPC）是一种与 EBV 相关的上皮恶性肿瘤，在东南亚和中国南方较为常见。尽管已经报道了多种基因和表观遗传改变，但失调信号通路对这种独特类型的头颈部癌症的贡献尚不清楚。在这里，我们证明了大多数 EBV 阳性肿瘤系和原发性肿瘤中 NOTCH 配体（JAG1 或 DLL4）和效应物（HEY1）的上调。在所有 EBV 阳性肿瘤系和 92.5%的原发性肿瘤中，NOTCH 受体中的 NOTCH3 过表达。在所有这些样本中均一致检测到 NOTCH3 信号的异常激活。这些发现表明 NOTCH3 可能在 NPC 的发生发展中发挥关键作用。通过 NOTCH3 特异性 siRNA，抑制 NOTCH3 信号，从而导致 NPC 细胞发生显著的生长抑制和凋亡诱导。在 NOTCH3 敲低的 NPC 细胞中，下调了一些参与细胞增殖的靶基因，如 CCND1、C-MYC、NFKB1 和存活的基因，如 BCL2、BCL-XL、SURVIVIN。重要的是，NOTCH3 敲低显著增强了 NPC 细胞对顺铂治疗的敏感性。此外，我们还发现，在敲低 NICD3 表达后，NPC 细胞在体外形成球体和在裸鼠中形成肿瘤的能力也显著降低。这些发现表明，NOTCH3 通路的激活是 NPC 肿瘤发生的关键致癌事件。靶向 NOTCH3 信号通路可能是治疗 EBV 相关 NPC 患者的一种潜在治疗方法。
