Purpose

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) constitutes the largest subpopulation in EBV-associated tumors worldwide. To date, 44 mature EBV-encoded microRNAs (EBV miRNAs) have been identified, but their roles in EBVaGC development are still poorly understood. In this study, we aimed to investigate the roles and targets of ebv-miR-BART10-3p (BART10-3p) and ebv-miR-BART22 (BART22) in EBVaGC.

Methods

EBV miRNA expression in EBVaGCs was evaluated by deep sequencing and qRT-PCR, and relationships between BART10-3p or BART22 expression and clinicolpathological characteristics and survival rates of patients with EBVaGC were analyzed. The roles of BART10-3p and BART22 and their underlying mechanisms were further investigated through exogenous overexpression or silencing in EBVaGC cells, and validated in clinical EBVaGC tissue samples.

Results

BART10-3p and BART22 were found to be highly expressed in the EBVaGC cell lines SNU719 and YCCEL1. Higher expression of BART10-3p or BART22 in primary EBVaGC samples was significantly associated with lymph node metastasis and a worse 5-year overall survival. BART10-3p and BART22 promoted cell migration and invasion by targeting adenomatous polyposis coli (APC) and Dickkopf 1 (DKK1), thereby activating the Wnt signaling pathway and, consequently, upregulating downstream Twist and downregulating downstream E-cadherin. In 874 primary gastric carcinoma samples, APC and DKK1 were found to be lower expressed in EBVaGC than in EBV-negative samples, and their expression levels were inversely correlated with those of BART10-3p and BART22 in 71 EBVaGC samples.

Conclusions

From our data we conclude that BART10-3p and BART22 play vital roles in promoting EBVaGC metastasis by targeting APC and DKK1 and, subsequently, activating the Wnt signaling pathway, thereby providing novel prognostic biomarkers and potential therapeutic targets for EBVaGC.

中文翻译：

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EBV-miR-BART10-3p和EBV-miR-BART22通过激活经典的Wnt信号通路促进与EBV相关的胃癌的转移。

目的

与爱泼斯坦巴尔病毒（EBV）相关的胃癌（EBVaGC）构成了全世界EBV相关肿瘤中最大的亚群。迄今为止，已鉴定出44种成熟的EBV编码的microRNA（EBV miRNA），但在EBVaGC发育中的作用仍知之甚少。在这项研究中，我们旨在研究ebv-miR-BART10-3p（BART10-3p）和ebv-miR-BART22（BART22）在EBVaGC中的作用和目标。

方法

通过深度测序和qRT-PCR评估EBVaGC中EBV miRNA的表达，并分析了BART10-3p或BART22表达与EBVaGC患者临床病理特征和生存率之间的关系。通过在EBVaGC细胞中外源性过表达或沉默进一步研究了BART10-3p和BART22的作用及其潜在机制，并在临床EBVaGC组织样品中进行了验证。

结果

发现BART10-3p和BART22在EBVaGC细胞系SNU719和YCCEL1中高表达。BART10-3p或BART22在主要EBVaGC标本中的高表达与淋巴结转移和较差的5年总生存率显着相关。BART10-3p和BART22通过靶向腺瘤性息肉病大肠杆菌（APC）和Dickkopf 1（DKK1）促进细胞迁移和侵袭，从而激活Wnt信号通路，并因此上调下游Twist和下调E-钙粘蛋白。在874例原发性胃癌样品中，发现APC和DKK1在EBVaGC中的表达低于在EBV阴性样品中，并且它们的表达水平与71份EBVaGC样品中的BART10-3p和BART22呈负相关。

结论

根据我们的数据，我们得出结论，BART10-3p和BART22通过靶向APC和DKK1，随后激活Wnt信号通路，在促进EBVaGC转移中起至关重要的作用，从而为EBVaGC提供新的预后生物标志物和潜在的治疗靶标。