Role of BamHI-A Rightward Frame 1 in Epstein–Barr Virus-Associated Epithelial Malignancies

Abstract

Epstein–Barr virus (EBV) infection is associated with a subset of both lymphoid and epithelial malignancies. During the EBV latency program, some viral products involved in the malignant transformation of infected cells are expressed. Among them, the BamHI-A rightward frame 1 (BARF1) is consistently detected in nasopharyngeal carcinomas (NPC) and EBV-associated gastric carcinomas (EBVaGCs) but is practically undetectable in B-cells and lymphomas. Although BARF1 is an early lytic gene, it is expressed during epithelial EBV latency, mainly as a secreted protein (sBARF1). The capacity of sBARF1 to disrupt both innate and adaptive host antiviral immune responses contributes to the immune escape of infected cells. Additionally, BARF1 increases cell proliferation, shows anti-apoptotic effects, and promotes an increased hTERT activity and tumor formation in nude mice cooperating with other host proteins such as c-Myc and H-ras. These facts allow for the consideration of BARF1 as a key protein for promoting EBV-associated epithelial tumors. In this review, we focus on structural and functional aspects of BARF1, such as mechanisms involved in epithelial carcinogenesis and its capacity to modulate the host immune response.

DNA immunotherapy targeting BARF1 induces potent anti-tumor responses against Epstein-Barr-virus-associated carcinomas

“…27,41,42 As the N-terminal domain of BARF1 can activate anti-apoptotic Bcl-2 expression and bind to M-CSF for immune modulation, domains or fragments of BARF1 that contain immune dominant B cell or T cell epitopes can be investigated for future studies. 14 For immunotherapy in humans, additional important antigens as part of an immune cocktail may be important. Combining BARF1 with other EBV-latent proteins, such as EBNA1, LMP1, and LMP2, could be considered for immunotherapy studies.…”

“…12,13 BARF1 is 221 amino acids in length and contains two immunoglobulin-like domains. 14 It is cleaved after the first 20 amino acids and secreted as a self-assembling hexamer (sBARF1). BARF1 contains interaction sites that allow it to bind to human macrophage colony stimulating factor (M-CSF) through its N-terminal domain and to human M-CSF-receptor homologous regions located in its C-terminal domain.…”

“…15 This interaction can reduce the expression of markers for macrophage differentiation such as CD11b, CD14, CD16, and CD169 and inhibit the production of interferon-alpha (IFN-a) by mononuclear cells, which is an important component of the host anti-viral immune response. 14 Other oncogenic effects of BARF1 include promoting cell proliferation, inducing cell immortalization, and anti-apoptosis. 16,17 Importantly, previous studies have demonstrated BARF1 to be immunogenic, as BARF1-specific antibodies and T cells were detected in some EBV + NPC patients.…”

Epstein–Barr Virus Infection in Lung Cancer: Insights and Perspectives

“…This is based on diverse studies in which some lytic proteins are consistently detected in cancers including Zta, Rta, and BARF1, among others [65]. In particular, BARF1 is an oncogenic early EBV protein with functions in immune evasion [66]. In latently infected B cells, lytic EBV promoters are methylated while they remain hypomethylated in normal oral keratinocytes (NOK) and Akata cells [67].…”

Human Papillomavirus in Breast Carcinogenesis: A Passenger, a Cofactor, or a Causal Agent?

“…However, LMP1 is absent [ 135 ] or weakly detected in EBV positive BCs [ 136 ], thus additional studies are warranted to explore the possibility of a E6/E7/LMP1 cooperation. A potential cooperation between HR-HPV E6/E7 oncoproteins and EBV BamHI-A rightward frame 1 (BARF1) protein presents itself as an interesting possibility to be evaluated in the future because BARF1 is considered an exclusively epithelial EBV oncogene [ 137 , 138 ].…”