Epstein–Barr virus latent antigens EBNA3C and EBNA1 modulate epithelial to mesenchymal transition of cancer cells associated with tumor metastasis
Epithelial–mesenchymal transition is an important mechanism in cancer invasiveness and metastasis. We had previously reported that cancer cells expressing Epstein–Barr virus (EBV) latent viral antigens EBV nuclear antigen EBNA3C and/ or EBNA1 showed higher motility and migration potential and had a propensity for increased metastases when tested in nude mice model. We now show that both EBNA3C and EBNA1 can modulate cellular pathways critical for epithelial to mesenchymal transition of cancer cells. Our data confirms that presence of EBNA3C or EBNA1 result in upregulation of transcriptional repressor Slug and Snail, upregulation of intermediate filament of mesenchymal origin vimentin, upregulation of transcription factor TCF8/ZEB1, downregulation as well as disruption of tight junction zona occludens protein ZO-1, downregulation of cell adhesion molecule E-cadherin, and nuclear translocation of β-catenin. We further show that the primary tumors as well as metastasized lesions derived from EBV antigen-expressing cancer cells in nude mice model display EMT markers expression pattern suggesting their greater propensity to mesenchymal transition.
KeywordsEBV Metastasis EMT EBNA3C
This work was supported by grants from the Department of Biotechnology of Government of India (BT/PR15109/GBD/27/320/2011), MRP grant from UGC (FN-41-1144/2012), R&D grant from the University of Delhi. NG is project fellow funded by UGC, and JG is senior research fellow funded by UGC. ESR is a scholar of the Leukemia and Lymphoma Society of America. SCV is funded by NIH public health grants (CA174459, AI105000). RK is UGC Indo-US Raman research fellow.
Conflicts of interest
- 3.Cai LM, Lyu XM, Luo WR, Cui XF, Ye YF, Yuan CC et al. EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN. Oncogene. 2014. doi:10.1038/onc.2014.341.Google Scholar
- 4.Chung TW, Kim SJ, Choi HJ, Song KH, Jin UH, Yu DY et al. Hepatitis B virus X protein specially regulates the sialyl lewis a synthesis among glycosylation events for metastasis. Mol Cancer. 2014;13:222. doi:10.1186/1476-4598-13-222.Google Scholar
- 5.Harakeh S, Abou-Khouzam R, Damanhouri GA, Al-Hejin A, Kumosani T, Niedzwiecki A et al. Effects of nutrients on matrix metalloproteinases in human T-lymphotropic virus type 1 positive and negative malignant T-lymphocytes. Int J Oncol. 2014;45(5):2159–2166.Google Scholar
- 6.Knight LM, Stakaityte G, Wood JJ, Abdul-Sada H, Griffiths DA, Howell GJ et al. Merkel cell polyomavirus small T antigen mediates microtubule destabilisation to promote cell motility and migration. J Virol. 2014. doi:10.1128/JVI.02317-14.Google Scholar
- 17.Lin Z, Wan X, Jiang R, Deng L, Gao Y, Tang J et al. EBV-encoded LMP2A Promotes EMT in Nasopharyngeal Carcinoma via MTA1 and mTOR Signaling Induction. J Virol. 2014. doi:10.1128/JVI.01867-14.Google Scholar
- 32.Hung SC, Kang MS, Kieff E. Maintenance of Epstein-Barr virus (EBV) oriP-based episomes requires EBV-encoded nuclear antigen-1 chromosome-binding domains, which can be replaced by high-mobility group-I or histone H1. Proc Natl Acad Sci U S A. 2001;98(4):1865–70.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Tuominen VJ, Ruotoistenmaki S, Viitanen A, Jumppanen M, Isola J. ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Breast Cancer Res.2010;12(4):R56.Google Scholar