Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells

Dong Ha Kim, Mee Soo Chang, Chan Jin Yoon, Jaap M Middeldorp, Olivia M Martinez, Sun-Ju Byeon, Sun Young Rha, Sung Han Kim, Yang Soo Kim, Jun Hee Woo

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)82213-82227
Number of pages15
JournalOncotarget
Volume7
Issue number50
DOIs
Publication statusPublished - 13 Dec 2016

Cite this

Kim, D. H., Chang, M. S., Yoon, C. J., Middeldorp, J. M., Martinez, O. M., Byeon, S-J., ... Woo, J. H. (2016). Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells. Oncotarget, 7(50), 82213-82227. https://doi.org/10.18632/oncotarget.10511
Kim, Dong Ha ; Chang, Mee Soo ; Yoon, Chan Jin ; Middeldorp, Jaap M ; Martinez, Olivia M ; Byeon, Sun-Ju ; Rha, Sun Young ; Kim, Sung Han ; Kim, Yang Soo ; Woo, Jun Hee. / Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 50. pp. 82213-82227.
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title = "Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells",
abstract = "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.",
keywords = "Epstein-Barr virus, BARF1, NF kappa B, miR-146a, SMAD4",
author = "Kim, {Dong Ha} and Chang, {Mee Soo} and Yoon, {Chan Jin} and Middeldorp, {Jaap M} and Martinez, {Olivia M} and Sun-Ju Byeon and Rha, {Sun Young} and Kim, {Sung Han} and Kim, {Yang Soo} and Woo, {Jun Hee}",
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Kim, DH, Chang, MS, Yoon, CJ, Middeldorp, JM, Martinez, OM, Byeon, S-J, Rha, SY, Kim, SH, Kim, YS & Woo, JH 2016, 'Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells' Oncotarget, vol. 7, no. 50, pp. 82213-82227. https://doi.org/10.18632/oncotarget.10511

Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells. / Kim, Dong Ha; Chang, Mee Soo; Yoon, Chan Jin; Middeldorp, Jaap M; Martinez, Olivia M; Byeon, Sun-Ju; Rha, Sun Young; Kim, Sung Han; Kim, Yang Soo; Woo, Jun Hee.

In: Oncotarget, Vol. 7, No. 50, 13.12.2016, p. 82213-82227.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells

AU - Kim, Dong Ha

AU - Chang, Mee Soo

AU - Yoon, Chan Jin

AU - Middeldorp, Jaap M

AU - Martinez, Olivia M

AU - Byeon, Sun-Ju

AU - Rha, Sun Young

AU - Kim, Sung Han

AU - Kim, Yang Soo

AU - Woo, Jun Hee

PY - 2016/12/13

Y1 - 2016/12/13

N2 - 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.

AB - 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.

KW - Epstein-Barr virus

KW - BARF1

KW - NF kappa B

KW - miR-146a

KW - SMAD4

U2 - 10.18632/oncotarget.10511

DO - 10.18632/oncotarget.10511

M3 - Article

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EP - 82227

JO - Oncotarget

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SN - 1949-2553

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