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Inhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV‐associated nasopharyngeal carcinoma
Author(s) -
Man CheukHim,
WeiMan Lun Samantha,
WaiYing Hui Jan,
To KaFai,
Choy KwongWai,
WingHung Chan Anthony,
Chow Chit,
TinYun Chung Grace,
Tsao SaiWah,
TakChun Yip Timothy,
Busson Pierre,
Lo KwokWai
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2997
Subject(s) - nasopharyngeal carcinoma , gene knockdown , cancer research , survivin , jag1 , notch signaling pathway , cyclin d1 , hedgehog signaling pathway , biology , cell culture , apoptosis , signal transduction , medicine , microbiology and biotechnology , cell cycle , genetics , radiation therapy , biochemistry
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. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.