EBV-miR-BART10-3p and EBV-miR-BART22 promote metastasis of EBV-associated gastric carcinoma by activating the canonical
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ORIGINAL PAPER
EBV-miR-BART10-3p and EBV-miR-BART22 promote metastasis of EBV-associated gastric carcinoma by activating the canonical Wnt signaling pathway Min Dong 1,2 & Li-ping Gong 1 & Jian-ning Chen 1 & Xiao-fang Zhang 1 & Yi-wang Zhang 1 & Da-yang Hui 1 & Xiao-xiao Zhao 1,3 & Xiang-yuan Wu 2 & Chun-kui Shao 1 Received: 22 June 2019 / Revised: 20 May 2020 / Accepted: 22 May 2020 # International Society for Cellular Oncology 2020
Abstract Purpose Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) constitutes the largest subpopulation in EBVassociated 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-miRBART10-3p (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. Keywords EBV-associated gastric carcinoma . Metastasis . microRNAs . ebv-miR-BART10-3p . ebv-miR-BART22 . Wnt signaling pathway
Min Dong and Li-ping Gong contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00538-0) contains supplementary material, which is available to authorized users. * Min Dong
1
Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou 510630, China
* Li-ping Gong
2
Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou 510630, China
3
Department of Pathology, Wuhan Central H
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