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 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.

The Wnt/β-catenin signalling pathway in Haematological Neoplasms

“…However, an increasing number of studies have shown that Epstein-Barr virus infection is closely related to the occurrence of lymphoma [89]. Mechanistic analysis showed that circEAF2 specifically targets EBVencoded miR-BART19-3p, upregulates APC, suppresses downstream β-catenin expression, and counteracts EBV + DLBCL progression [90]. By regulating the nuclear translocation of β-catenin, long noncoding RNAs play a substantial role in the development of lymphoma.…”

Circular RNA and Its Roles in the Occurrence, Development, Diagnosis of Cancer

“…Furthermore, Zhao et al. reported that CircEAF2 inhibited Epstein-Barr infection positive diffuse large B cell expansion and advanced apoptosis via the miR-BART19-3p/APC/-catenin axis ( 170 ).…”

Past, Present and Future: The Relationship Between Circular RNA and Immunity

“…Zhao et al. proposed that circEAF2 counteracts Epstein–Barr virus-positive diffuse large B-cell lymphoma progression via the miR-BART19-3p/APC/β-catenin axis ( 110 ). Regarding the regulated proteins, CXCR4 ( 111 – 113 ), APC ( 114 – 116 ), etc., served as important regulators in the Wnt signaling pathway.…”