Epstein-Barr Virus MicroRNA miR-BART5-3p Inhibits p53 Expression

Abstract

Epstein-Barr virus (EBV) is the first human virus found to encode many microRNAs. It is etiologically linked to nasopharyngeal carcinoma and EBV-associated gastric carcinoma. During the latent infection period, there are only a few EBV proteins expressed, whereas EBV microRNAs, such as the BamHI-A region rightward transcript (BART) microRNAs, are highly expressed. However, how these BART miRNAs precisely regulate the tumor growth in nasopharyngeal carcinoma and gastric carcinoma remains obscure. Here, we report that upregulation of EBV-miR-BART5-3p promotes the growth of nasopharyngeal carcinoma and gastric carcinoma cells. BART5-3p directly targets the tumor suppressor gene on its 3'-untranslated region (3'-UTR) and consequently downregulates, , and expression, leading to acceleration of the cell cycle progress and inhibition of cell apoptosis. BART5-3p contributes to the resistance to chemotherapeutic drugs and ionizing irradiation-induced p53 increase. Moreover, BART5-3p also facilitates degradation of p53 proteins. BART5-3p is the first EBV-microRNA to be identified as inhibiting p53 expression and function, which suggests a novel mechanism underlying the strategies employed by EBV to maintain latent infection and promote the development of EBV-associated carcinomas. EBV encodes 44 mature microRNAs, which have been proven to promote EBV-associated diseases by targeting host genes and self-viral genes. In EBV-associated carcinomas, the expression of viral protein is limited but the expression of BART microRNAs is extremely high, suggesting that they could be major factors in the contribution of EBV-associated tumorigenesis. p53 is a critical tumor suppressor. Unlike in most human solid tumors, TP53 mutations are rare in nasopharyngeal carcinoma and EBV-associated gastric carcinoma tissues, suggesting a possibility that some EBV-encoded products suppress the functions of p53. This study provides the first evidence that a BART microRNA can suppress p53 expression by directly targeting its 3'-UTR. This study implies that EBV can use its BART microRNAs to modulate the expression of p53, thus maintaining its latency and contributing to tumorigenesis.

Epstein-Barr Virus Nuclear Antigen 1 Recruits Cyclophilin A to Facilitate the Replication of Viral DNA Genome

“…EBV latent infection is an important causative factor in the development of related cancers such as NPC (Dittmer et al, 2008;Zheng et al, 2014Zheng et al, , 2018, although the mechanism is largely unclear. Viral replication and genome maintenance in host cells are important for the pathogenesis.…”

Gastric cancer: genome damaged by bugs

“…BART3-3p plays an important role in inhibiting the senescence of GC cells by targeting TP53 [134]. As for apoptosis, it was reported that BART5-3p directly targets TP53, leading to acceleration of the cell cycle progress and inhibition of cell apoptosis [135]. Besides, EBV encoded miR-BART5 could target p53 upregulated modulator of apoptosis (PUMA), which is a proapoptotic protein belonging to the Bcl-2 family, to counteract apoptosis and promote cellular survival [136].…”

“…Activates NF-κB-survivin pathway to rescue EBV-infected epithelial cells from serum deprivation [122] Regulates cyclin E expression and S phase cell ratio [123] Elevates mitochondrial fission and promotes cellular migration through Notch pathway [124] Downregulates HLA to evade immune response [125] Activates phosphatidylinositol 3-kinase/Akt pathways to mediate transformation and inhibits transforming growth factor-beta 1-induced apoptosis [126,127] Promotes cell malignant by inducing epigenetic changes of host genome [129] Upregulates miR-155-5p, and targets Smad2 and p-Smad2 to regulate TGF-β pathway [128] miR-BARTs miR-BART9 decreases E-cadherin expression and upregulates proliferation [133] miR-BART3-3p inhibits the senescence of gastric cancer cells by targeting TP53 [134] miR-BART5-3p targets the tumor-suppressor gene TP53, leading to acceleration of the cell cycle progress and inhibition of cell apoptosis [135] miR-BART5 targets PUMA, counteracts apoptosis and promotes cellular survival [136] miR-BART9, 11, and 12 downregulate Bim expression [137] miR-BART4-5p suppresses the proapoptotic protein Bid to regulate apoptosis [138] miR-BART20-5p interacts with 3'UTR of BAD to contribute to tumorigenesis [139] miR-BART16 suppresses type I IFN signaling [140] with clinical outcome. MSI subtype has the best prognosis and lowest recurrence rate followed by MSS/TP53 + and MSS/TP53 − , while the MSS/EMT subtype demonstrates the worst prognosis and highest recurrence rate among the four subtypes.…”

Epstein–Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer

“…We recently reported another BART microRNA, BART5-3p, that can directly target TP53 by combining with TP53 3Ј-UTR, thereby promoting the progression of EBV-positive epithelial tumors (38). Unlike BART5-3p, BART3-3p binds to the TP53 CDS region but not 3Ј-UTR (Fig.…”