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.

Highlights

  • In 2014, molecular analytic data from The Cancer Genome Atlas (TCGA) corroborated that Epstein-Barr virus (EBV)-associated stomach cancer is a specialized subset of stomach cancer [1]

  • nuclear factor κB (NFκB) luciferase activity was higher in SNU601 BamHI-A rightward frame 1 (BARF1) cells than in SNU601 mock cells (P < 0.05), and NFκB activity was lower in small interfering RNA (siRNA) against BARF1 (siBARF1)-transfected YCCEL1 cells than in scrambled siRNA-transfected control YCCEL1 cells (P < 0.01)

  • We examined the association of miR-146a-5p, a cellular miRNA, with NFκB. miR-146a-5p levels were significantly higher in SNU601 BARF1 cells than in SNU601 mock cells (P < 0.01), and miR-146a-5p was downregulated in siBARF1-transfected YCCEL1 cells compared with scrambled siRNA-transfected control (P < 0.01) (Figure 2C)

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Summary

Introduction

In 2014, molecular analytic data from The Cancer Genome Atlas (TCGA) (http://cbioportal.org) corroborated that Epstein-Barr virus (EBV)-associated stomach cancer is a specialized subset of stomach cancer [1]. EBV is responsible for various human lymphoid and epithelial malignancies [1, 2, 3] including EBV-infected stomach cancer, which was first reported in 1990 [4]. Stomach cancer is the most frequent EBV-associated malignancy [5, 6]. Over the last 25 years, accumulating evidence www.impactjournals.com/oncotarget has shown that EBV infection may directly contribute to the development of stomach cancer. EBV-positive stomach cancer shows characteristic clinicopathological features, including a higher prevalence in male patients, predominant localization to the proximal stomach, a tendency towards a poorly differentiated histologic type and a diffuse Laurentype, the presence of lymphoid stroma [1, 9,10,11], and a unique cellular protein expression profile [12]

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