The copy number of Epstein-Barr virus latent genome correlates with the oncogenicity by the activation level of LMP1 and NF-κB
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Lielian Zuo1,2, Haibo Yu2,4, Lingzhi Liu2, Yunlian Tang2,5, Hongzhuan Wu3, Jing Yang1,2, Meijuan Zhu2, Shujuan Du2, Lian Zhao2,6, Li Cao2, Guiyuan Li1,2, Jianhong Lu1,2
1Central Laboratory, Hunan Provincial Tumor Hospital, the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, China
2Cancer Research Institute, the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
3Department of Biological Sciences, Alabama State University, Montgomery, AL 36101, USA
4Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
5Current address: Cancer Research Institute, University of South China, Hengyang, Hunan 421001, China
6Current address: Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
Jianhong Lu, e-mail: [email protected]
Keywords: Epstein–Barr virus, latent genome, copy number, latent membrane protein 1, oncogenicity
Received: May 28, 2015 Accepted: September 15, 2015 Published: October 16, 2015
A tumor model that Epstein-Barr virus (EBV) latent infection facilitated the tumorigenicity was previously established using the Maxi-EBV system. In the present approach, EBV-lost cell clones demonstrated significantly decreased tumorigenesis. On the other hand, the LMP1 gene in Maxi-EBV genome was replaced by that of nasopharyngeal carcinoma origin. The resultant cell line, 293–1/NL showed much lower malignancy than the original 293-EBV. The result was opposite to our expectation. The change of 293 sublineage cells for EBV harboring also got similar result. To seek the underlying reason, the copy number of EBV genome in all the cell lines was detected. The result indicated that 293-EBV contained about 4.5-fold higher EBV copies than 293–1/NL did. Parallel EBV genomes led to relatively stable copies in different 293 sublineages, suggesting the viral genome structure is a factor for the sustainability of EBV’s copy number. Moreover, the LMP1 transcription in high copy-containing cells showed abnormally high level. Furthermore, the main LMP1-driven pathway, transcription factor NF-κB, was highly activated in high-copy cells. Here we first manifest by experimental model that the copy number of EBV latent genome correlates with the viral pathogenesis, which depends on the activation level of LMP1 and NF-κB. Overall, both the presence and amount of EBV genome are crucial for the viral oncogenicity.
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