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EBV-miR-BART10-3p and EBV-miR-BART22 promote metastasis of EBV-associated gastric carcinoma by activating the canonical Wnt signaling pathway

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Abstract

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81572309 to CKS, and No. 81502271 to MD), the Natural Science Foundation of Guangdong Province (No. 2017A030313502 to CKS), and Guangzhou Municipal Science and Technology Project (No. 201707010119 to CKS). We thank Prof. Qian Tao from the Chinese University of Hong Kong for supplying the YCCEL1 cell line as gift. We also thank Prof. Ling Xue from the First Affiliated Hospital, Sun Yat-sen University, Prof. Hai-gang Li from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Prof. Yan Huang from the Sixth Affiliated Hospital, Sun Yat-sen University, and Prof. Hong Du from Guangzhou First People’s Hospital, Guangzhou Medical University for providing gastric carcinoma tissue samples.

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  1. Min Dong and Li-ping Gong contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China

    Min Dong, Li-ping Gong, Jian-ning Chen, Xiao-fang Zhang, Yi-wang Zhang, Da-yang Hui, Xiao-xiao Zhao & Chun-kui Shao

  2. Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China

    Min Dong & Xiang-yuan Wu

  3. Department of Pathology, Wuhan Central Hospital, Wuhan, 430014, China

    Xiao-xiao Zhao

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Dong, M., Gong, Lp., Chen, Jn. et al. EBV-miR-BART10-3p and EBV-miR-BART22 promote metastasis of EBV-associated gastric carcinoma by activating the canonical Wnt signaling pathway. Cell Oncol. 43, 901–913 (2020). https://doi.org/10.1007/s13402-020-00538-0

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