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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-12-01
|
| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-021-01458-9 |
| _version_ | 1818838123678793728 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T03:33:24Z |
| format | Article |
| id | doaj.art-c7b7bd250b1b40caab40ce02069b0b7d |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-19T03:33:24Z |
| publishDate | 2021-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-c7b7bd250b1b40caab40ce02069b0b7d2022-12-21T20:37:27ZengBMCMolecular Cancer1476-45982021-12-0120111710.1186/s12943-021-01458-9CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axisChen-xing Zhao0Zi-xun Yan1Jing-jing Wen2Di Fu3Peng-peng Xu4Li Wang5Shu Cheng6Jian-da Hu7Wei-li Zhao8Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union HospitalShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineFujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union HospitalShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineFujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union HospitalShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1186/s12943-021-01458-9Epstein-Barr virusDiffuse large B-cell lymphomacircEAF2miR-BART19-3pWnt signaling pathwayβ-catenin |
| spellingShingle | 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 Molecular Cancer Epstein-Barr virus Diffuse large B-cell lymphoma circEAF2 miR-BART19-3p Wnt signaling pathway β-catenin |
| title | 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_short | 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 |
| topic | Epstein-Barr virus Diffuse large B-cell lymphoma circEAF2 miR-BART19-3p Wnt signaling pathway β-catenin |
| url | https://doi.org/10.1186/s12943-021-01458-9 |
| work_keys_str_mv | AT chenxingzhao circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT zixunyan circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT jingjingwen circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT difu circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT pengpengxu circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT liwang circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT shucheng circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT jiandahu circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis AT weilizhao circeaf2counteractsepsteinbarrviruspositivediffuselargebcelllymphomaprogressionviamirbart193papcbcateninaxis |