Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells
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Dong Ha Kim1,2,*, Mee Soo Chang3,*, Chan Jin Yoon1,2, Jaap M. Middeldorp4, Olivia M. Martinez5, Sun-ju Byeon3, Sun Young Rha6, Sung Han Kim1,2, Yang Soo Kim1,2, Jun Hee Woo1,2
1Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
2Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
3Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
4Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
5Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA
6Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
* These authors have contributed equally to this work
Mee Soo Chang, email: email@example.com
Jun Hee Woo, email: firstname.lastname@example.org
Keywords: Epstein-Barr virus, BARF1, NFκB, miR-146a, SMAD4
Received: January 11, 2016 Accepted: May 12, 2016 Published: July 09, 2016
Epstein-Barr virus (EBV)-encoded BamHI-A rightward frame 1 (BARF1) is a putative viral oncogene in EBV-infected stomach cancer. The aim of the present study was to investigate BARF1-induced cellular protein and microRNA alterations. In this study, BARF1-expressing stomach cancer cells showed a high rate of proliferation, high levels of NFκB, and miR-146a upregulation, which was reversed by NFκB knockdown. During BARF1-induced NFκB upregulation, hCSF1 receptor level was unchanged. Knockdown of BARF1 in the naturally EBV-infected YCCEL1 stomach cancer cells suppressed cell proliferation, and downregulated NFκB and miR-146a. SMAD4 was identified as a miR-146a target and was downregulated in BARF1-expressing cells, whereas SMAD4 expression was restored by anti-miR-146a. Knockdown of BARF1 in YCCEL1 cells upregulated SMAD4, and this effect was reversed by miR-146a overexpression. Transfection of BARF1-expressing cells with pCEP4-SMAD4 abolished the cell proliferating effect of BARF1. In stomach cancer tissues, miR-146a was expressed at higher levels, and more frequent NFκB nuclear positivity immunohistochemically, but not of SMAD4 nuclear loss was found in the EBV-positive group compared with the EBV-negative group. In conclusion, EBV-encoded BARF1 promotes cell proliferation in stomach cancer by upregulating NFκB and miR-146a and downregulating SMAD4, thereby contributing to EBV-induced stomach cancer progression.
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