BARF1 gene silencing triggers caspase-dependent mitochondrial apoptosis in Epstein-Barr virus-positive malignant cells

Mohidin, Taznim Begam Mohd; Ng, Ching Ching

doi:10.1007/s12038-015-9502-z

Cited by 12 publications

(13 citation statements)

References 35 publications

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“…[13][14][15][16] BARF1, a secretory protein, is a homolog to the human proto-oncogene c-fms, and plays a role in the malignant transformation of EBV-positive cells. [17,18] In addition, it is part of EBV's immune evasion strategies since it binds to human macrophage colony stimulating factor (M-CSF). [19,20] Here, to investigate the immunogenicity of BARF1, we used an unbiased, peptide library approach to assess the frequency of BARF1-specific T cells in EBV-seropositive healthy donors and patients with EBV-associated malignancies.…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy

et al. 2019

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Background: EBV type II latency tumors such as Hodgkin lymphoma (HL), Non-Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma (NPC) express a limited array of EBV antigens including Epstein-Barr nuclear antigen (EBNA)1, latent membrane protein (LMP)1, LMP2, and BamH1-A right frame 1 (BARF1). Adoptive immunotherapy for these malignancies have focused on EBNA1, LMP1, and LMP2 since little is known about the cellular immune response to BARF1. Methods: To investigate if BARF1 is a potential T-cell immunotherapy target, we determined the frequency of BARF1-specific T-cell responses in the peripheral blood of EBV-seropositive healthy donor and patients with EBV-positive malignancies, mapped epitopes, and evaluated the effector function of ex vivo generated BARF1-specific T-cell lines. Results: BARF1-specific T cells were present in the peripheral blood of 12/16 (75%) EBVpositive healthy donors and 13/20 (65%) patients with EBV-positive malignancies. Ex vivo expanded BARF1-specific T-cell lines contained CD4-and CD8-positive T-cell subpopulations, and we identified 23 BARF1 peptides, which encoded MHC class I-and/or II-restricted epitopes. Epitope mapping identified one HLA-A*02-restricted epitope that was recognized by 50% of HLA-A*02, EBV-seropositive donors, and one HLA-B*15(62)-restricted epitope. Ex vivo

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Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy

et al. 2019

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“…EBV-encoded BamHI-A rightward frame 1 (BARF1) was suggested to function as a viral oncogene (oncogenic initiator or oncogenic cofactor) in EBV-positive stomach cancer [5, 17–19]. It has been demonstrated that BARF1 exists in all of EBV-positive stomach cancer tissues with a specialized BARF1-nucleic acid sequence-based amplification (NASBA) method using frozen tissue [19].…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells

et al. 2016

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Epstein-Barr virus (EBV)-encoded BamHI-A rightward frame 1 (BARF1) is a putative viral oncogene in EBV-infected stomach cancer. The aim of the present study was to investigate BARF1-induced cellular protein and microRNA alterations. In this study, BARF1-expressing stomach cancer cells showed a high rate of proliferation, high levels of NFκB, and miR-146a upregulation, which was reversed by NFκB knockdown. During BARF1-induced NFκB upregulation, hCSF1 receptor level was unchanged. Knockdown of BARF1 in the naturally EBV-infected YCCEL1 stomach cancer cells suppressed cell proliferation, and downregulated NFκB and miR-146a. SMAD4 was identified as a miR-146a target and was downregulated in BARF1-expressing cells, whereas SMAD4 expression was restored by anti-miR-146a. Knockdown of BARF1 in YCCEL1 cells upregulated SMAD4, and this effect was reversed by miR-146a overexpression. Transfection of BARF1-expressing cells with pCEP4-SMAD4 abolished the cell proliferating effect of BARF1. In stomach cancer tissues, miR-146a was expressed at higher levels, and more frequent NFκB nuclear positivity immunohistochemically, but not of SMAD4 nuclear loss was found in the EBV-positive group compared with the EBV-negative group. In conclusion, EBV-encoded BARF1 promotes cell proliferation in stomach cancer by upregulating NFκB and miR-146a and downregulating SMAD4, thereby contributing to EBV-induced stomach cancer progression.

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“…BARF1 reportedly functions as a viral oncogene that up‐regulates anti‐apoptotic Bcl‐2 and stimulates host cell growth and survival . BARF1 knockdown up‐regulates the expression of pro‐apoptotic proteins and down‐regulates the expression of anti‐apoptotic proteins . Moreover, BARF1 promotes cancer cell survival by increasing the Bcl‐2 to Bax ratio .…”

Section: The Interplay Of Ebv Lytic Reactivation and Radioresistancementioning

confidence: 99%

“…77 BARF1 knockdown up-regulates the expression of pro-apoptotic proteins and down-regulates the expression of anti-apoptotic proteins. 18 Moreover, BARF1 promotes cancer cell survival by increasing the Bcl-2 to Bax ratio. 22 Based on the current evidence, the expression of BHRF1 or BARF1 during EBV lytic reactivation might increase their ability to function as survival factors to resist apoptosis and contribute to radioresistance.…”

Section: Ebv-encoded Products Resist Cell Death and Might Confer Radimentioning

confidence: 99%

The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications

Luo

et al. 2017

Intl Journal of Cancer

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Epstein-Barr virus (EBV) is an important cancer causing virus. Cancer associated with EBV account for approximately 1.5% of all cancers, and represent 1.8% of all cancer deaths worldwide. EBV reactivation plays an important role in the development of EBV-related diseases and is closely related with patients' survival and clinical stages of EBV-related cancers. The therapy regarding to EBV-related cancers is very urgent, especially in endemic areas. Generating oxidative stress is a critical mechanism by which host cells defend against infection by virus. In addition, ROS-mediated oxidative stress plays a significant but paradoxical role acting as a "double-edged sword" to regulate cellular response to radiation, which is the main therapy strategy for EBV-related cancers, especially nasopharyngeal carcinoma. Therefore, in this review we primarily discuss the possible interplay among the oxidative stress, EBV lytic reactivation and radioresistance. Understanding the role of oxidative stress in EBV lytic reactivation and radioresistance will assist in the development of effective strategies for prevention and treatment of EBV-related cancers.

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BARF1 gene silencing triggers caspase-dependent mitochondrial apoptosis in Epstein-Barr virus-positive malignant cells

Cited by 12 publications

References 35 publications

Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy

Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy

Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells

The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications

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