Inhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV-associated nasopharyngeal carcinoma.
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.
Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR.
Cheuk-Him
CH
Man
Samantha
S
Wei-Man Lun
Jan
J
Wai-Ying Hui
Ka-Fai
KF
To
Kwong-Wai
KW
Choy
Anthony
A
Wing-Hung Chan
Chit
C
Chow
Grace
G
Tin-Yun Chung
Sai-Wah
SW
Tsao
Timothy
T
Tak-Chun Yip
Pierre
P
Busson
Kwok-Wai
KW
Lo
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D055785:Gene Knockdown Techniques; D052138:Genes, Neoplasm / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000821:virology; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018874:Spheroids, Cellular / Q000502:physiology; D014162:Transfection; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; C499373:Notch3 protein, mouse; D034741:RNA, Small Interfering; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D002945:Cisplatin