Epstein-Barr virus latent membrane protein 2A suppresses the expression of HER2 via a pathway involving TWIST and YB-1 in Epstein-Barr virus-associated gastric carcinomas.

Yi-Wang Zhang,Xiao-Xiao Zhao,Hai-Gang Li,Ling Xue,Hong Du,Jian-Ning Chen,Cui Tan,Chun-Kui Shao,Zhi-Gang Zhang,Ye Jiang,Hong-Bo Wei

doi:10.18632/oncotarget.2702

Abstract

To explore HER2 expression in Epstein-Barr virus-associated gastric carcinoma (EBVaGC) and the possible mechanisms causing down-regulation of HER2 expression in EBVaGC, we first evaluated HER2 and LMP2A expression on a clinicopathological-features matched cohort including 78 EBVaGC and 216 EBV-negative gastric carcinoma (EBVnGC) cases by immunohistochemistry. Cases with high HER2 expression in EBVaGC were significantly less than in EBVnGC (5.1% versus 23.7%; p<0.001), and none of the 34 LMP2A+ EBVaGC showed high HER2 expression. Further, overexpressing LMP2A in EBV-negative SGC7901 cells significantly decreased HER2, TWIST and YB-1 mRNA by 36.1%±8.1%, 87.6%±14.0% and 83.8%±5.7%, and protein by 44%, 57% and 49%, respectively. Additionally, the nucleus/cytoplasm ratios of TWIST and YB-1 were also decreased by 85% and 80%, respectively. Silencing LMP2A by siRNA in EBV-positive SNU719 cells for 48 h significantly increased HER2, TWIST and YB-1 mRNA to 276.7%±14.6%, 1284.8%±38.2% and 332.0%±15.5% and protein to 212%, 457% and 232%, respectively. The nucleus/cytoplasm ratios of TWIST and YB-1 were up-regulated by 4.00- and 3.57-fold, respectively, following LMP2A down-regulation. Moreover, LMP2A+/HER2low EBVaGC cases presented the best overall survival compared with LMP2A-/HER2low and LMP2A-/HER2high cases (p=0.003, log-rank test). These results suggest that LMP2A may suppress the HER2 expression through the TWIST/YB-1 axis in EBVaGC.

Highlights

Epstein-Barr virus (EBV) is a ubiquitous human herpes virus that causes a life-long asymptomatic persistent infection in more than 95% of the human population [1]
Camargo MC et al have reported that Epstein-Barr virus-associated gastric carcinoma (EBVaGC) exhibited a significantly longer survival time compared with EBV-negative gastric carcinoma (EBVnGC) [10,11], while van Beek et al and Huang SC et al observed no difference in overall survival between EBVaGC and EBVnGC [12,13]
We found that Human epidermal growth factor receptor-2 (HER2) expression is significantly reduced in EBVaGC compared with EBVnGC

Summary

Introduction

EBV is a ubiquitous human herpes virus that causes a life-long asymptomatic persistent infection in more than 95% of the human population [1]. EBV is thought to be closely associated with the development of some lymphoid neoplasms, nasopharyngeal carcinoma (NPC) and EBVaGC [2,3]. EBVaGC comprise approximately 10% of all gastric carcinomas worldwide with a frequency ranging from 1.3% to 20.1% in different countries [6,7]. Our previous study suggested that the proportion of EBVaGC in gastric carcinoma in Guangzhou, southern China, where NPC is endemic, was 6.7% (45/676) [8]. EBVaGC has several distinct clinicopathological features, such as being highly associated with the male gender and younger individuals, www.impactjournals.com/oncotarget presenting generally diffuse-type histology and frequently occurring in the gastric cardia and body [5,9]. Previous studies have not reached a consensus on the prognosis for EBVaGC. Camargo MC et al have reported that EBVaGC exhibited a significantly longer survival time compared with EBVnGC [10,11], while van Beek et al and Huang SC et al observed no difference in overall survival between EBVaGC and EBVnGC [12,13]

Methods

Results

Conclusion