Inhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV-associated nasopharyngeal carcinoma

Authors

  • Cheuk-Him Man,

    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
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    • These authors contributed equally to this study.

  • Samantha Wei-Man Lun,

    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
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    • No conflicts of interest were declared.

  • Jan Wai-Ying Hui,

    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
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  • Ka-Fai To,

    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
    2. Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, SAR
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  • Kwong-Wai Choy,

    1. Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
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  • Anthony Wing-Hung Chan,

    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
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  • Chit Chow,

    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
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  • Grace Tin-Yun Chung,

    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
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  • Sai-Wah Tsao,

    1. Department of Anatomy, University of Hong Kong, SAR
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  • Timothy Tak-Chun Yip,

    1. Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, SAR
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  • Pierre Busson,

    1. Laboratoire de Biologie des Tumeurs Humaines, Institut Gustave Roussy, Villejuif, France
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  • Kwok-Wai Lo

    Corresponding author
    1. Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, SAR
    2. Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, SAR
    • Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.
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Abstract

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.

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