CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis

Abstract Background Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mec...

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Autores principales:	Chen-xing Zhao, Zi-xun Yan, Jing-jing Wen, Di Fu, Peng-peng Xu, Li Wang, Shu Cheng, Jian-da Hu, Wei-li Zhao
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Epstein-Barr virus Diffuse large B-cell lymphoma circEAF2 miR-BART19-3p Wnt signaling pathway β-catenin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c7b7bd250b1b40caab40ce02069b0b7d
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spelling	oai:doaj.org-article:c7b7bd250b1b40caab40ce02069b0b7d2021-12-05T12:03:23ZCircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis10.1186/s12943-021-01458-91476-4598https://doaj.org/article/c7b7bd250b1b40caab40ce02069b0b7d2021-12-01T00:00:00Zhttps://doi.org/10.1186/s12943-021-01458-9https://doaj.org/toc/1476-4598Abstract Background Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown. Methods CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting. Results We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream β-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth. Conclusions CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/β-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.Chen-xing ZhaoZi-xun YanJing-jing WenDi FuPeng-peng XuLi WangShu ChengJian-da HuWei-li ZhaoBMCarticleEpstein-Barr virusDiffuse large B-cell lymphomacircEAF2miR-BART19-3pWnt signaling pathwayβ-cateninNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Cancer, Vol 20, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Epstein-Barr virus Diffuse large B-cell lymphoma circEAF2 miR-BART19-3p Wnt signaling pathway β-catenin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Epstein-Barr virus Diffuse large B-cell lymphoma circEAF2 miR-BART19-3p Wnt signaling pathway β-catenin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Chen-xing Zhao Zi-xun Yan Jing-jing Wen Di Fu Peng-peng Xu Li Wang Shu Cheng Jian-da Hu Wei-li Zhao CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis
description	Abstract Background Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown. Methods CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting. Results We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream β-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth. Conclusions CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/β-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.
format	article
author	Chen-xing Zhao Zi-xun Yan Jing-jing Wen Di Fu Peng-peng Xu Li Wang Shu Cheng Jian-da Hu Wei-li Zhao
author_facet	Chen-xing Zhao Zi-xun Yan Jing-jing Wen Di Fu Peng-peng Xu Li Wang Shu Cheng Jian-da Hu Wei-li Zhao
author_sort	Chen-xing Zhao
title	CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis
title_short	CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis
title_full	CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis
title_fullStr	CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis
title_full_unstemmed	CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis
title_sort	circeaf2 counteracts epstein-barr virus-positive diffuse large b-cell lymphoma progression via mir-bart19-3p/apc/β-catenin axis
publisher	BMC
publishDate	2021
url	https://doaj.org/article/c7b7bd250b1b40caab40ce02069b0b7d
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CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis

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