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Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor-?-activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-?B pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-?B pathway through TAK1 activation.

SUBMITTER: Noujima-Harada M

PROVIDER: S-EPMC5448608 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Noujima-Harada Mai M Takata Katsuyoshi K Miyata-Takata Tomoko T Sakurai Hiroaki H Igarashi Kazuhiko K Ito Etsuro E Nagakita Keina K Taniguchi Kohei K Ohnishi Nobuhiko N Omote Shizuma S Tabata Tetsuya T Sato Yasuharu Y Yoshino Tadashi T

Cancer science 20170424 5

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative p ...[more]

PMID: 28256087

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Project description:Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), is a rare malignancy of Non-Hodgkin lymphoma characterized by an aggressive clinical course and poor prognosis. It shows strong association with Epstein-Barr virus infection and occurs more commonly in Asia and Latin America. Various genetic alterations have been identified in ENKL by gene expression profiling and sequencing techniques. The frequent deletion of chromosome 6q21 was reported to lead to the silence of several tumor suppressor genes. Also, there have been novel genetic mutations that were recently uncovered and were found to frequently activate several oncogenic pathways, including the JAK/STAT, NF-?B, and MAPK pathways. Besides, we believe that deregulated single genes and epigenetic dysregulation might be relevant to the mechanism of this disease and thus, may have the potential to shed lights on the development of new therapeutic strategies. The consensus on the standard treatment for ENKL has not yet been currently established. For localized ENKL patients, radiotherapy with concurrent chemotherapy and sequential patterns of chemotherapy and radiotherapy are recommended as first-line therapy. As for advanced or relapsed/refractory ENKL patients, the application of non-anthracycline-containing regimens have significantly improved the clinical outcome, contributing to higher response rate, longer overall survival and progression-free survival. Hematopoietic stem cell transplantation is widely recommended for consolidation after a complete remission or partial remission has been achieved. The anti-programmed death 1 antibody, an immune checkpoint inhibitor, has demonstrated favorable results in treating relapsed or refractory ENKL. Of the current ENKL treatment, researchers are still striving to validate how radiotherapy and chemotherapy should be optimally combined and which of the non-anthracycline-containing regimens is superior. In this review, we summarize the main genetic alterations frequently found in ENKL and their role in providing new insights into the therapeutic targets of this disease, and highlight the recent findings regarding new biologic markers, novel therapeutic strategies applied to this intriguing neoplasm.

Project description:BackgroundEpstein-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.MethodsCircRNA 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.ResultsWe 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.ConclusionsCircEAF2 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.

Dataset Information

Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Publications

Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

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