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Establishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma.

ABSTRACT: The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole-exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC.

SUBMITTER: Lin W

PROVIDER: S-EPMC6220246 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Establishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma.

Lin Weitao W Yip Yim Ling YL Jia Lin L Deng Wen W Zheng Hong H Dai Wei W Ko Josephine Mun Yee JMY Lo Kwok Wai KW Chung Grace Tin Yun GTY Yip Kevin Y KY Lee Sau-Dan SD Kwan Johnny Sheung-Him JS Zhang Jun J Liu Tengfei T Chan Jimmy Yu-Wai JY Kwong Dora Lai-Wan DL Lee Victor Ho-Fun VH Nicholls John Malcolm JM Busson Pierre P Liu Xuefeng X Chiang Alan Kwok Shing AKS Hui Kwai Fung KF Kwok Hin H Cheung Siu Tim ST Cheung Yuk Chun YC Chan Chi Keung CK Li Bin B Cheung Annie Lai-Man AL Hau Pok Man PM Zhou Yuan Y Tsang Chi Man CM Middeldorp Jaap J Chen Honglin H Lung Maria Li ML Tsao Sai Wah SW

Nature communications 20181107 1

The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NP ...[more]

PMID: 30405107

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Project description:BackgroundNonviral vectors are attractively used for gene therapy owing to their distinctive advantages. Our previous study has demonstrated that transfer of human IFN? gene into nasopharyngeal carcinoma (NPC) by using a novel nonviral vector, minicircle (mc), under the control of cytomegalovirus (CMV) promoter was effective to inhibit tumor growth. However, therapies based on CMV promoter cannot express the targeted genes in cancer tissues. Previous studies indicated that the development of human NPC was closely associated with Epstein-Barr virus (EBV) and demonstrated the transcriptional enhancer function of oriP when bound by EBV protein. Therefore, the present study is to explore the targeted gene expression and the anti-tumor effect of a novel tumor-specific gene therapeutic system (mc-oriP-IFN?) in which the transgene expression was under the transcriptional regulation of oriP promoter.Methodology/principal findingsDual-luciferase reporter assay and ELISA were used to assess the expression of luciferase and IFN?. WST assay was used to assess the cell proliferation. RT-PCR was used to detect the mRNA level of EBNA1. RNAi was used to knockdown the expression of EBNA1. NPC xenograft models in nude mice were used to investigate the targeted antitumor efficacy of mc-oriP-IFN?. Immunohistochemistry was used to detect the expression and the activity of the IFN? in tumor sections. Our results demonstrated that mc-oriP vectors mediated comparable gene expression and anti-proliferative effect in the EBV-positive NPC cell line C666-1 compared to mc-CMV vectors. Furthermore, mc-oriP vectors exhibited much lower killing effects on EBV-negative cell lines compared to mc-CMV vectors. The targeted expression of mc-oriP vectors was inhibited by EBNA1-siRNA in C666-1. This selective expression was corroborated in EBV-positive and -negative tumor models.Conclusions/significanceThis study demonstrates the feasibility of mc-oriP-IFN? as a safe and highly effective targeted gene therapeutic system for the treatment of EBV positive NPC.

Dataset Information

Establishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma.

Publications

Establishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma.

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