EBV-miR-BHRF1-1 Targets p53 Gene: Potential Role in Epstein-Barr Virus Associated Chronic Lymphocytic Leukemia

Abstract

PurposeThe purpose of this study was to investigate the prognostic impact of Epstein-Barr virus (EBV)–microRNA (miRNA, miR)-BHRF1-1 with chronic lymphocytic leukemia (CLL) as well as role of EBV-miR-BHRF1-1 in p53 gene.Materials and MethodsQuantitative reverse transcription–polymerase chain reaction and western blotting were used to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL.Resultsp53 aberration was associated with the higher expression level of EBV-miR-BHRF1-1 (p < 0.001) which was also an independent prognostic marker for overall survival (p=0.028; hazard ratio, 5.335; 95% confidence interval, 1.193 to 23.846) in 97 newly-diagnosed CLL patients after adjusted with International Prognostic Index for patients with CLL. We identified EBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressed luciferase reporter activity by specific interaction with the seed region within the p53 3′- untranslated region. Discordance of p53 messenger RNA and protein expression was associated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1- 1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosis and decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53 protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferation in cell lines.ConclusionThis study supported the role of EBV-miR-BHRF1-1 in p53 regulation in vitro. Our results support the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLL with p53 gene aberration.

BHRF1-1 MicroRNA of Epstein Barr Virus in Chronic B-Lymphocytic Leukemia Patients

“…We discovered that the levels of EBV miRNA BHRF1-1 expression in the B-cells of CLL cases were substantially greater than in healthy ones. The expression of BHRF1-1 in CLL cases ranged from 0.31 -9.0 with a median (IQR) of 3.63 (2.12 -4.44) and in control group from 0.02 -1.30 with a median (IQR) of 0.31 (0.13 -0.81), that in line with similar findings demonstrated by Visco et al [25] and Xu et al [26] who found CLL patients had greater EBV-BHRF1-1 levels than the healthy control group. This finding is consistent with earlier research and is owing to its essential involvement in B-cell differentiation and the prevention of apoptotic processes.…”

EBV-Positive Gastric Cancer: Current Knowledge and Future Perspectives

“…Tumor protein p53, or simply p53, is closely related to the occurrence of gastric cancer, and many studies find EBV infection to be associated with p53 methylation (21)(22)(23). In 2019, Camargo et al found that EBV-positive gastric cancer cases lack the TP53 mutation, suggesting that serological characteristics may provide information for viral carcinogenesis.…”

Landscape of EBV-positive gastric cancer

“…Several predicted targets of EBV-encoded miR-NAs were detected by computational prediction, and some of these were functionally investigated using an in vitro assay [36]. BHRF1 miRNAs, which encode three pri-miRNAs, show almost undetectable expression in EBV (+) GC; thus, their functional roles in lytic infection, in regulating host cell cycle and viral infection, and in progeny production, were revealed in various types of malignancy rather than in GC [37][38][39][40][41][42][43][44][45]. In GC specifically, BART miRNAs encoding 44 mature miRNAs may disrupt genes involved in apoptosis and cell cycle regulation, as confirmed in EBV (+) GC (Table 1) [2,10,36,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59].…”