Next Article in Journal
Annexins in Glaucoma
Next Article in Special Issue
Noncoding RNA:RNA Regulatory Networks in Cancer
Previous Article in Journal
Identification, Expression Analysis of the Hsf Family, and Characterization of Class A4 in Sedum Alfredii Hance under Cadmium Stress
Previous Article in Special Issue
The Double Face of Exosome-Carried MicroRNAs in Cancer Immunomodulation
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Role of miRNAs in Virus-Mediated Oncogenesis

Department of Genetics and Microbiology, Faculty of Science, Charles University, Průmyslová 595, Vestec, CZ-25250, 128 44 Prague, Czech Republic
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(4), 1217; https://doi.org/10.3390/ijms19041217
Submission received: 27 February 2018 / Revised: 12 April 2018 / Accepted: 13 April 2018 / Published: 17 April 2018
(This article belongs to the Special Issue The Role of MicroRNAs in Human Diseases)

Abstract

:
To date, viruses are reported to be responsible for more than 15% of all tumors worldwide. The oncogenesis could be influenced directly by the activity of viral oncoproteins or by the chronic infection or inflammation. The group of human oncoviruses includes Epstein–Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), human herpesvirus 8 (HHV-8) or polyomaviruses, and transregulating retroviruses such as HIV or HTLV-1. Most of these viruses express short noncoding RNAs called miRNAs to regulate their own gene expression or to influence host gene expression and thus contribute to the carcinogenic processes. In this review, we will focus on oncogenic viruses and summarize the role of both types of miRNAs, viral as well as host’s, in the oncogenesis.

Graphical Abstract

1. Introduction

More than 14 million cancer cases are diagnosed each year worldwide, with more than 15% attributable to the carcinogenic infections [1]. Oncoviruses are responsible for more than 63% of cases, the bacterium Helicobacter pylori accounts for 35%, and the remaining 2% of cases are associated with three parasites (Schistosoma haematobium, Opisthorchis viverrini and Clonorchis sinensis). In 2000, Hanahan and Weinberg identified six hallmarks of cancer—evading antigrowth signals, tissue invasion and metastasis, enabling replicative immortality, sustained angiogenesis, evading apoptosis, and maintaining proliferative signaling [2]. In 2011, these principles were updated by adding another four, including deregulated cellular energetics, avoiding of immunological destruction, tumor-promoting inflammation, and genomic instability and mutations [3]. Oncoviruses, as infectious agents, can induce all of these hallmarks and thus contribute to tumor development through multiple pathways. However, it is important to mention that in viral oncogenesis, viruses are necessary but not sufficient to cause cancer, so the incidence of cancer is much lower than the prevalence of the causative viruses [4].
The oncogenic viruses evoke and maintain persistent infection during which they are hidden from the immune system, which is compatible with carcinogenic processes. Most oncogenic viruses have mechanisms through which they are equally segregated into the daughter cells during cell division, and thus their genome is maintained in the host cells during proliferation. The virus-mediated cell immortalization is then influenced either directly or indirectly. The direct mechanisms include the deregulated expression of cellular oncogenes/tumor-suppressor genes, influenced by integration of the viral genome into the host genome (e.g., retroviruses, human papillomaviruses, hepatitis B viruses), or the expression of viral oncogenes (e.g., herpesviruses) which inactivate major regulators of genome stability and cell cycle leading to DNA damage and transformation of the host cell. The indirect mechanisms of transformation comprise the tissue damage caused by immune cells and chronic inflammation, or establishment of immunosuppression due to viral infection, resulting in the inhibition of antitumor surveillance mechanisms.
Oncogenic viruses are represented in all groups of viruses. The most relevant are DNA viruses, of which we should mention Epstein–Barr Virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), human herpesvirus 8 (HHV-8), or polyomaviruses. The group of RNA viruses is represented by hepatitis C virus (HCV), and finally, the group of retroviruses includes transregulating viruses such as human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV-1).
MicroRNAs (miRNAs) are short noncoding RNAs of ~21 nucleotides in length which post-transcriptionally regulate gene expression and have an important role in the development, cell growth, differentiation processes, survival, or regulation of apoptosis in a variety of eukaryotic organisms [5]. It is suggested that the expression of at least one third of human genes is influenced by miRNAs [6], and the deregulated expression of miRNAs has been observed in many types of tumors [7,8]. However, most of the oncogenic viruses also express miRNAs to regulate their own gene expression or to influence host gene expression, and thus contribute to the carcinogenic processes. Even though many new virus-encoded miRNAs were discovered in the last 15 years, only a minority of them were shown to fulfill the criteria for authentic viral miRNAs. These criteria are very important when deep-sequencing techniques are applied, since many small non-viral RNAs can be detected. Besides the number of miRNA copies per cell, identification of the region in the viral genome from which the miRNA is derived, the size of the miRNA within the range of 19–25 bases, the specificity of the 5′ end, and identification of the hairpin structure of pre-miRNA should be specified for an authentic viral miRNA [9]. In this review, we will more closely focus on the role of viral miRNAs in oncogenesis and on the impact of their expression on the hosts. Moreover, the role of the host’s miRNA expression during oncogenesis will be discussed.

2. Epstein–Barr Virus

Epstein–Barr Virus (EBV, HHV-4), the first oncovirus discovered, is classified as a DNA virus from the family Herpesviridae. It was detected first in Burkitt lymphoma (BL) cells in 1964 [10], and this discovery started the research on the virus-mediated oncogenesis. The primary infection of EBV is most common in childhood, and then EBV persists in latent form mostly in resting memory B-cells and less commonly in T-cells, NK-cells, or epithelial cells [11]. Besides Burkitt lymphoma, EBV is associated with other B-cell lymphoproliferative disorders such as Hodgkin lymphoma (HL) or post-transplant lymphoproliferative disorder (PTLD), with T-cell lymphoproliferative disorders or epithelial malignancies such as gastric carcinoma and nasopharyngeal carcinoma (NPC) [12,13,14].
The mechanism of EBV-mediated carcinogenesis is the coding of the viral oncoproteins. The main oncoprotein is latent membrane protein 1 (LMP1), which is a transmembrane protein functionally mimicking CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily. The activation of this receptor leads to the initiation of the signaling pathways such as phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription proteins (JAK/STAT) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), leading to B-cell differentiation towards memory B-cells, expression of anti-apoptotic proteins, and increased cell proliferation [15]. Oncoprotein LMP2 is structurally and functionally similar to the B-cell receptors (BCRs) which, after phosphorylation, activate the non-receptor tyrosine kinase (Src) and spleen tyrosine kinase (Syk) signaling pathways and thus increases the survival of latently infected B-cells by production of cytokines such as interleukin 10 (IL-10) and by expression of anti-apoptotic factors [16,17,18]. EBV nuclear antigen 1 (EBNA1) is a multifunctional protein which influences viral replication, transcription and latency. As the only one of the nuclear proteins, it is expressed in both lytic and latent phases of the viral life cycle [19]. EBNA1 suppresses the function of the promyelocytic leukemia (PML) protein, which is a tumor suppressor protein regulating p53 activation. Thus, EBNA1 inhibits p21 activation and signaling, leading to inhibition of apoptosis and cell survival [20]. EBNA-LP (EBNA leader protein) functions in cooperation with EBNA2, and both proteins participate in initiating the transcription of viral and cellular proteins responsible for B-cell immortalization and transformation, for example, cellular gene c-myc [21]. Finally, EBNA-3 proteins associate with many cellular proteins from different signaling pathways such as recombination signal binding protein for immunoglobulin kappa J region (RBP-Jκ) and thus contribute to increased proliferation and transformation of B-cells [22].
EBV was the first virus for which the viral-encoded miRNAs were described. Pfeffer et al. have published the report describing viral-encoded miRNAs from cell lines infected with EBV [23]. These five miRNAs were encoded in two clusters, BHRF1 (miR-BHRF1-1, miR-BHRF1-2, miR-BHRF1-3) and BART (miR-BART1 and miR-BART2). Nowadays, according to the miRBase database, EBV encodes 25 pre-miRNAs producing at least 44 mature miRNAs [24]. The benefit of viral-encoded miRNAs, not only for EBV but for all viruses coding their own miRNAs, is the ability to regulate viral as well as host gene expression without the production of viral proteins, allowing for the immune invisibility of the infected cells.
As mentioned above, EBV miRNAs have been reported to regulate their own expression. BART miRNAs (miR-BART16, -17-5p, -1-5p) target viral transcripts for protein LMP1 and thus contribute to cell transformation [25]. MiR-BART22 negatively regulates translation of LMP2A in NPC and thus helps EBV-infected cells to escape the host immune surveillance [26]. EBV also uses the miRNAs for indirect regulation of the switch between the lytic and latent life phases. For example, miR-BART2 regulates DNA polymerase BALF5 and helps to replicate the viral genome in the lytic phase, and thus its negative regulation promotes the latent stage of the virus [27]. Iizasa et al. have reported miR-BART6-5p to regulate the viral replication and latency through suppressing the EBNA2 viral oncogene [28].
EBV miRNAs also regulate the translation of host mRNAs and thus may influence cancer development. MiR-BART5-5p and miR-BART19-5p negatively regulate the translation of p53 upregulated mediator of apoptosis (PUMA) protein, a factor that positively influences cellular apoptosis and was found at significantly lower levels in NPC cells infected by EBV compared to noninfected ones [29]. Nasopharyngeal carcinoma cells were analyzed also by Cai et al. [30], and they revealed that miR-BART7-3p promotes the epithelial–mesenchymal transition (EMT) and metastasis through suppressing the major human tumor suppressor PTEN, which modulates PI3K/Akt/GSK-3β signaling. Vereide et al. revealed that miR-BART1 and miR-BART16 help to block apoptosis in BL cells in the absence of other viral oncogenes through their targeting of caspase 3 (Casp3) [31]. Infected cells thus survive, and the virus may replicate. Further, the EBV miRNA miR-BART3 has been reported to negatively regulate the expression of the cellular tumor suppressor DICE1 (determination of interleukin 4 commitment 1), which was found downregulated in NPC cells, leading to increased proliferation and transformation of the cells [32]. EBV also uses its own miRNAs for the immune evasion strategy. MiR-BHRF1-3 targets the mRNA of host interferon-inducible cytokine CXCL11 [33]. Targeted suppression of this cytokine may serve as an immunomodulatory mechanism in EBV-associated tumors. In-vitro studies have demonstrated that the action of miR-BHRF1 enhances the B-cell transformation and decreases the antigen loading of cells [34]; however, in-vivo studies have revealed that miR-BHRF1 facilitates the development of acute infection but does not enhance the oncogenic potential [35]. The evasion of the host immune system is also mediated by miR-BART2-5p, which negatively regulates the expression of major histocompatibility complex (MHC) class I chain-related protein B (MICB) molecules upregulated on the infected cells’ surface and recognized by NK cells [36]. The expression of EBV-encoded miRNAs may also influence the survival of patients with EBV-associated cancer. A high level of miR-BART20-5p was associated with worse survival of patients with EBV-related gastric cancer [37]. Moreover, the expression of viral miR-BART7 predicted the responsiveness of NPC cells to radiation treatment because of its targeting of the glutamine fructose-6-phosphate transaminase 1/transforming growth factor beta 1 (GFPT1/TGFβ1) signaling, regulating the DNA damage repair machinery [38].
The deregulation of cellular miRNA expression is a feature detectable in many human tumors including EBV-associated tumors. It has been reported that EBV infection of primary B-cells results in downregulation of cellular miRNA expression [39]. Iizasa et al. have revealed that EBV miR-BART6-5p suppresses the expression of Dicer and thus influences expression of many miRNAs as well as miR-BART6-5p itself by a negative feedback loop [28]. The tumor suppressor miR-31 is consistently inactivated in NPC, since it targets the MCM2 protein and inhibits the growth of NPC cells [40]. Nevertheless, many cellular miRNAs are upregulated due to the infection, such as miR-155, which promotes the proliferation and migration of NPC cells [41] or B-cell immortalization [42]. The aberrant expression of miR-155 is driven by EBV LMP1 and LMP2A [43,44], and its upregulated expression in EBV-associated tumors was also confirmed by the study of Sakamoto et al. [45], who used a next-generation sequencing approach. The miRNA related to EBV infection in BL is miR-127, which was not found in EBV-negative BL, and it contributes to the development of lymphoma through the blocking of BLIMP-1 or XBP-1, regulators of B-cell differentiation [46]. MiR-21, a very important oncomiR in tumor development, was found to be positively regulated by EBV EBNA2 protein in B-cell lymphoma [47], and in tumors has anti-apoptotic and prometastatic roles. The EBNA2 protein further negatively regulates the expression of miR-146a, a miRNA involved in the innate immune response [47]. Oussaief et al. [48] have shown that LMP1 protein expression triggered downregulation of the miR-183-96-182 cluster, whose expression is downregulated in BL cell lines and has a key role in EBV-mediated transformation. Finally, Chen et al. [49] have revealed that the expression of miR-1 in NPC is downregulated by LMP1. This miRNA functions as a tumor suppressor by regulating K-ras (Kirsten rat sarcoma) gene expression with pro-apoptotic effect and inhibition of the angiogenesis during tumor development.

3. HHV-8

Another oncovirus from the family Herpesviridae is human herpesvirus 8 (HHV-8). Sometimes it is called Kaposi’s sarcoma-associated herpesvirus (KSHV) since it is a causal agent of Kaposi’s sarcoma (KS), a proliferative disease of vascular and lymphatic endothelial cells [50]. HHV-8 infection mainly manifests in immunocompromised patients, such as those with AIDS and those after transplantation or chemotherapy. Apart from KS, HHV-8 causes primary effusion lymphoma (PEL) [51] or multicentric Castleman’s disease [52], with both affecting B-cells. HHV-8 influences the proliferation and cell cycle of the infected cells due to the sequence homology with host genes. In the latent phase of the viral infection, viral cyclin D (v-cyclin D) and LANA1 regulating the cell cycle, viral FLICE inhibition protein (v-FLIP)—inhibitor of apoptosis, kaposins, or viral interferon response factors (vIRF) modulating the immune system and influencing the proliferation—are expressed.
KSHV encodes 12 viral pre-miRNAs, which evolve into 25 mature miRNAs. All miRNA genes are clustered together and are under the control of latent kaposin promoter (LTd). Most of the pre-miRNA genes are intronic, located between the sequence for kaposin and open reading frame (ORF) 71, except for miR-K10, which is located within the ORF of kaposin, and miR-K12 located on the 3′ end of the kaposin gene [53]. It is important to mention that viral latency is critical for tumor development. KSHV miRNAs participate in the regulation of the viral life cycle targeting directly key viral genes as well as indirectly, through cellular genes regulating viral replication and thus contributing to the oncogenesis. The viral miRNAs miR-K9-5p and miR-K7-5p are modulators of the latent–lytic switch as they target the viral RTA (R transactivator) protein, the regulator of lytic induction [54,55]. The viral life cycle is also regulated by miR-K3, which targets cellular nuclear factor I/B and thus negatively influences the expression of RTA [56], or by G-protein-coupled receptor kinase 2 (GRK2), enhancing in this way the viral latency [57]. The expression of RTA could also be restrained by the activity of miR-K12-11 which targets cellular myeloblastosis transcription factor (MYB) [58], previously reported to be an activator of the RTA promoter [59]. Moreover, miR-K12-11 modulates interferon signaling through targeting I-kappa-B kinase epsilon (IKKε), contributing to the maintenance of viral latency [60]. The latent phase of the viral infection is also maintained by methylation of the RTA promoter, which is ensured by DNA methyl transferase 1 (DNMT1) [61]. The activity of this methyltransferase is regulated by KSHV miR-K12-4-5p, which inactivates its suppressor retinoblastoma-like protein 2 (Rbl2), affecting cell cycle and cellular differentiation control.
KSHV miRNAs play roles also in the dissemination and angiogenesis of KS. Several miRNAs, such as miR-K12-1, miR-K3-3p, miR-K6-3p, or miR-K12-11, negatively regulate the expression of thrombospondin 1 (THBS1), which is an antagonist of angiogenesis, and its downregulation leads to abnormal angiogenesis and proliferation of KSHV-infected cells [62]. Another miRNA promoting dissemination and angiogenesis is miR-K6-3p, whose activity stimulates the STAT3 pathway leading to cell migration and the invasion of KS cells [63]. As has been shown by Guo et al. [64], KSHV miRNAs regulate matrix metalloproteinases (MMPs) and expression of pro-angiogenic factors, and thus play roles in KSHV-induced cell motility and angiogenesis. KSHV miRNAs help to promote the development of KS and other KSHV-associated malignancies through the cell cycle arrest, cell survival, and cell transformation. Zhu et al. have reported that KSHV promotes these processes by suppressing the aerobic glycolysis and oxidative phosphorylation under nutrient stress [65]. They have revealed that KSHV regulates the key metabolic pathways of the cells by miRNAs to adapt to the tumor microenvironment. MiR-K12-1 is an anti-apoptotic miRNA, which downregulates the expression of protein p21, the inhibitor of cyclin-dependent kinases and a key inducer of cell cycle arrest [66], and in this way, contributes to the survival of viral-transformed cells. Also, miR-K12-1, miR-K12-3, and miR-K12-4-3p, which inactivate the critical inducer of apoptosis, caspase 3 (Casp3), participate in inhibition of apoptosis and thus play a role in KSHV-induced oncogenesis [67].
Like EBV, KSHV influences the expression and function of cellular miRNAs. Viral miR-K12-11, playing a role in PEL development, shares the seed sequence with the cellular miR-155, whose targets affect B-cell differentiation, and thus regulates a set of common mRNA targets [68,69]. Tsai et al. have revealed that KSHV protein K15 via the viral SH2-binding motif contributes to KSHV-associated tumor metastasis and angiogenesis by regulation of cellular miR-21 and miR-31 [70]. The KSHV-encoded protein vFLIP K13 activates the NF-κB pathway, suppressing the expression of cytokine C-X-C chemokine receptor type 4 (CXCR4) through upregulation of cellular miR-146a [71]. CXCR4 plays a key role in the retention of immature endothelial cells in the marrow, and its downregulation contributes to premature release of these cells into the circulation and to KS development. Only one study analyzing the miRNA expression profiles in KSHV-infected B-cells has been published so far. Hussein and Akula performed the analysis of the early stages of KSHV infection of human B-cells and have revealed 32 known and 28 novel differentially expressed miRNAs [72]. The potential biological implications of the known differentially expressed miRNAs included promoting cell survival and latent infection, inhibiting the host immune response, or inducing critical cell signaling.

4. Hepatitis B Virus

Hepatitis B virus (HBV) belongs to the family Hepadnaviridae and causes an acute liver disease—viral hepatitis. Most infected adults recover completely in a few months, but about 5% of the adult patients proceed to chronic infection [11], which can consequently develop into hepatocellular carcinoma (HCC). In patients infected perinatally or in childhood, the percentage of chronic infection is higher (90% and 20% of cases, respectively). HBV is the third most frequent infectious agent contributing to cancer development, with 420,000 of new cancer cases reported in 2012 [1]. Apart from HCC, HBV infection is associated with B-cell non-Hodgkin lymphoma (B-NHL) [73] and nasopharyngeal carcinoma (NPC) [74], but the exact virus-associated pathogenesis is still unclear.
The HBV genome encodes four ORFs, which consist of genes for surface proteins (preS1, preS2 and S), genes for core (core and precore) proteins, genes for polymerase, and genes for protein HBx. The oncogenesis is influenced by the direct mechanisms of the virus such as activity of viral oncoprotein HBx or surface proteins in the transcriptional regulation, regulation of DNA repair or expression of miRNAs [75,76,77,78], and/or the integration of the viral DNA into the host genome in the proximity of the fragile sites [79,80]. Further, HBV contributes to the development of the tumors by indirect mechanisms, such as chronic inflammation and activation of protumorigenic signaling pathways [81].
The presence and the function of HBV-encoded miRNAs has so far not been proven, but at least two published studies suggested existence of HBV-specific miRNAs, and we discuss them below. On the other hand, numerous studies focused on the cellular miRNA profiles and their deregulation during HBV-associated tumorigenesis have been described. Highly specific to hepatocytes is miR-122, which maintains the differentiated phenotype of cells, and its downregulation was observed in HCC cell lines as well as in clinical samples. MiR-122 negatively regulates the expression of a tumor promoter, N-myc downstream-regulated gene 3 (NDRG3) [82], or pituitary tumor-transforming gene 1 (PTTG1) binding factor (PBF) whose upregulation, because of the loss of miR-122 expression, leads to the cell growth and invasion of the HCC tumor [83]. The tumor cell growth is also regulated by cyclin G1, whose expression increases depending on the suppression of miR-122 [84]. Song et al. [85] have revealed that the reduction of the miR-122 level in HCC cells is due to the protein–protein activity of viral HBx protein with peroxisome proliferator activated receptor-gamma (PPARγ), which normally enhances the miR-122 transcription by binding to its promoter. Besides miR-122, protein HBx further influences the expression of cellular miR-29a, which is upregulated in HBx-transfected hepatoma cells and whose upregulation positively correlates with the metastatic potential [86]. MiR-29a increases the migration ability of cells through targeting tumor suppressor phosphatase and tensin homolog (PTEN) and activation of the Akt signaling pathway. MiR-29a/b also targets MHC class I chain-related protein A (MICA) or MICB, whose decreased expression results in a limited activity of natural killer (NK) cells and promotion of chronic infection [87]. Moreover, HBx decreases the level of miR-101, enhancing tumorigenesis through epigenetic silencing of tumor suppressor genes (TSGs) [88]. This miRNA targets DNA methyltransferase 3A (DNMT3A), which catalyzes the methylation of TSG promoter regions and thus inhibits their expression. DNA methylation is also influenced through HBx downregulation of miR-152, which targets DNA methyltransferase 1 (DNMT1) and epigenetically regulates the expression of TSGs [89]. Not only miRNAs mediate epigenetic modifications of DNA, but also the protein HBx itself induces DNA methylation of promoter. Wei et al. [90] have revealed that HBx induces DNA hypermethylation of the miR-132 promoter and thus promotes cell proliferation through the Akt signaling pathway. Moreover, they have found that the serum levels of miR-132 correlate with that in the tumor tissues, implicating that it might be a noninvasive candidate for a diagnostic biomarker of HBV-related HCC. Protein HBx also negatively regulates the level of miRNA let-7a [91]. These tumor suppressor miRNAs are involved in cell differentiation and proliferation through the STAT signaling pathway, and are often downregulated in HCC. Also, a decreased level of let-7a leads to the activation of proliferation factors, such as Ras [92] or Myc [93]. Let-7 expression might also be regulated by HBx indirectly through the upregulation of the let-7 inhibitors LIN28A and LIN28B [94,95].
Profiling studies of virus-related HCC search for miRNAs specific for the early stages of the tumors or progression of the disease. Mizuguchi et al. [96] have used next-generation sequencing and bioinformatics to reveal the miRNA transcriptome of HBV-related HCC. The global profiling of miRNAs in HBV-related HCC was also performed by Wang et al. [97], who analyzed 12 pairs of HCC and matched nonmalignant tissues from HBV-positive and HBV-negative patients. They have revealed eight miRNAs involved in HCC unrelated to virus, a further five miRNAs involved in HBV infection, and finally, seven miRNAs specifically altered in HBV-associated HCC. The possible role of these miRNAs (miR-150, miR-342-3p, miR-663, miR-20b, miR-92a-3p, miR-376c-3p, and miR-92b) in HBV-related HCC development must be further investigated.
Not only viruses can influence the expression of cellular miRNAs and thus the development of the tumor, but also host miRNAs regulate the viral life cycle and replication and thus affect the progression of chronic hepatitis to HCC. Direct targeting of HBV mRNA, by transcript of gene HBx, was observed by Wang et al. [98]. They have found that the tumor suppressors miR-15a/miR-16-1 target viral mRNA and thus reprogram the expression of multiple cellular miRNAs including these miRNAs themselves, leading to the HCC development. A similar negative feedback suppression was observed by Jung et al. [99] for cluster miR-17-92. Finally, Chen et al. [100] have revealed that miR-122 downregulates HBV replication by binding to the viral target sequence contributing to chronic HBV infection.

5. Human Papillomavirus

The human papillomaviruses (HPVs), double-stranded DNA tumor viruses, belong to the family Papillomaviridae. HPVs infect epithelial cells of the skin or mucosa and may cause benign proliferations such as papillomas or warts. Further, some types of HPVs also have an oncogenic potential and are the main etiologic factor or cofactor in a variety of carcinomas. HPVs are the most frequent viral agents involved in oncogenesis attributable to infectious agents, with almost 640,000 new cases in 2012 [1]. HPVs cause almost 100% of cervical cancers. HPVs participate in oncogenesis in other anogenital regions, such as vulvar, penile, or anal area, and in the development of head and neck cancer; however, the global burden of HPV-associated cancer in these anatomical locations is substantially lower [1].
The genome of HPV is composed of early-region genes E1–E7, a late region with two capsid proteins L1 and L2, a long control region (LCR) with regulatory sequences, and a viral origin of replication. Some types of HPV also express the E8^E2C fusion protein [101,102,103]. Viral early-region proteins E6 and E7 are the main oncoproteins in HPVs, and their overexpression contributes to tumor development. The E5 viral protein has a high transformation potential in bovine papillomavirus 1 (BPV1) [104]. In HPVs, the presence of E5 in the viral genome correlates with the risk of cancer, and E5 cooperates with the main viral oncoproteins E6 and E7 [105,106]. Protein E6 inactivates the function of tumor suppressor p53 [107,108], while protein E7 binds the retinoblastoma protein Rb and thus activates cell cycle progression [109]. The virus might incorporate into the host genome and thus enhance the malignant progression. The integration is an important event in HPV-related carcinogenesis, whose frequency depends on the stage of disease, HPV type, and type of HPV-associated tumor [110], but it is not obligatory for cell transformation.
Profiling of miRNA expression in HPV-associated malignancies has been done in numerous studies with the aim to define new biomarkers for the detection of premalignant stages of the disease as well as markers for selection of patients for modified treatments [111]. Since HPV-associated tumors are etiologically distinct from viral-unrelated tumors of the same anatomical location, for the interpretation of the data, it is important whether the studies also specify the viral status. For cervical cancer, numerous such studies have been published [112,113,114,115], while for head and neck tumors, the information about the viral status has not been commonly evaluated [111,116,117,118,119,120,121]. The knowledge about tumor viral status is specifically very important for head and neck tumors where only 20–90% of them are HPV-associated [122,123].
The process of how the HPV oncoproteins affect the expression of cellular miRNAs was studied by Harden et al. [124], who have assumed that the modulation of the cellular miRNA expression is the main oncogenic activity of these proteins and have suggested several mRNA–miRNA pairs as potential drivers of HPV carcinogenesis. The miR-106b~25 cluster is one of those regulated by transcription factors of the E2F family (transcription factors of higher eukaryotes) and thus by HPV E7 [125]. Furthermore, the expression of the miR-15b~16-2 cluster or the miR-34 family is regulated by HPV oncoproteins [126,127] leading to cell cycle progression and contributing to tumor development. The expression of miR-23b has been shown to be downregulated by the action of the viral E6 protein, resulting in an increase in a direct miRNA target, urinary plasminogen activator (uPA), and thus promoting tumor cell migration [128]. The expression of miR-9 has been found upregulated in both cervical and tonsillar tumors [119,121]. The activation of miR-9 increases cell motility and has been shown to be involved in the pathways regulating metastasis [129,130]. Downregulation of miR-218, identified in cervical cancer as well as in head and neck cancers, has been shown to promote cell migration and invasion [131,132]. While the expression of miR-375 was also found downregulated in cervical tumors [133], it functions as a tumor suppressor by targeting HPV transcripts. This leads to the repression of the expression of E6/E7, cell cycle arrest, and reduced proliferation of HPV-positive cervical cancer cells.

6. Merkel Cell Polyomavirus

Polyomaviruses are nonenveloped DNA viruses belonging to the family Polyomaviridae which infect a number of hosts, such as birds or mammals. It was long considered that humans could only be infected by JC and BK polyomaviruses; nevertheless, up to now, at least 11 more human polyomaviruses have been identified, including Merkel cell polyomavirus (MCPyV). MCPyV was discovered to be associated with human cancer in 2008 [134], and since then, the interest in polyomavirus research has increased. Whereas MCPyV was detected in more than 90% of Merkel cell carcinomas (MCCs) [135,136], the oncogenic properties of JCPyV and BKPyV have only been documented in cell cultures and animal models [137]. Only scarce studies suggest their oncogenic potential in humans [138,139,140].
The oncoproteins that drive the virus-mediated oncogenesis are early-coded large T (LT) antigen and small T (ST) antigen [141]. Besides these early antigens, MCPyV encodes two more early proteins, the 57kT antigen and alternative LT open reading frame (ALTO), and three late-coded proteins, VP1-3. The first polyomaviral miRNA was described in polyomavirus SV40 [142]; it is encoded on the 3′ end of the late transcript and is complementary to early viral mRNAs. The authors have shown that it reduces the cytotoxic T-lymphocyte-mediated cell lysis and interferon gamma (INF-γ) release. Later, JCV-miR-J1 has been identified in JCPyV and BKV-miR-B1 in BKPyV [143]. These two miRNAs function as inhibitors of NK-cell response [144]. In 2009, MCV-miR-M1 was discovered in MCPyV [145]. All these viral miRNAs influence the expression of LT antigen and thus regulate the viral life cycle and contribute to the host immune evasion.
As documented in previous chapters, miRNAs encoded by oncogenic viruses contribute to the tumorigenesis; however, no human polyomaviral miRNAs have yet been implicated in this process. In tumors, MCPyV miRNAs are not detected or are detected in very low levels (<0.025%) [146,147], because MCPyV DNA is integrated into the host genome in most tumors [134,148]. Therefore, only early genes are expressed, whilst PyV miRNAs are encoded from the late transcripts that are expressed during lytic infection. However, this is in contrast with the study of Chen et al. [149], who chose phylogenetically-related raccoon PyV (RacPyV) to investigate the function of PyV miRNA in tumors. Despite the genomic and sequence similarities of RacPyV miRNA with MCPyV miRNA, high levels of early gene transcripts and miRNA levels have been detected in RacPyV-associated tumors [149,150]. Thus, their observations suggest that these PyV-associated tumors arise via different mechanisms, and MCPyV miRNA probably is not involved in MCC tumorigenesis. Therefore, only future research will reveal the role of PyV miRNAs in virus-mediated carcinogenesis.
The effect of LT antigen on the cellular miRNA expression has not yet been investigated; however, the control of host miRNA expression by the LT antigen is assumed, since this protein is involved, among others, in transcriptional regulation of cellular genes, affects RNA polymerase II-dependent transcription, and thus, might influence the production of pri-miRNAs [137]. The only study to analyze the cellular miRNA expression profiles was that of Xie et al. [151], who compared the miRNA profiles in MCPyV-positive and MCPyV-negative MCC. As expected, they have revealed distinct patterns and have found miR-203, miR-30a, miR-769-5p, miR-34a, and miR-375 to be significantly deregulated. In addition, the authors tested the functional consequences of the overexpression of miR-203 in MCC and have revealed that it functions as a tumor suppressor since it inhibits the cell growth, induces cell cycle arrest, and regulates survivin expression in MCC cells non-associated with MCPyV [151].

7. Hepatitis C Virus

Hepatitis C virus (HCV) belongs to the family Flaviviridae and is the only representative of the RNA viruses group that is associated with the development of tumors. HCV affects hepatocytes and causes acute infection, which progresses to chronic disease in 75–80% of cases, thus increasing the risk of cirrhosis and/or hepatocellular carcinoma (HCC) [152]. HCV might also contribute to the development of several other malignancies, such as pancreatic or renal cancer and B-cell non-Hodgkin lymphoma [153]. HCV is the fourth leading infectious agent contributing to carcinogenesis, with almost 8% of new cases of cancer being attributable to infection in 2012 [1]. The HCV genome is a positive RNA strand which encodes structural proteins (Core, E1 and E2) and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B). HCV-associated oncogenesis is promoted by both direct and indirect mechanisms [154]. The direct mechanisms involve primarily the activity of viral proteins, such as core and nonstructural proteins, that promote tumorigenesis through interaction with cell factors leading to the activation of tumorigenic pathways and cell transformation, and the indirect mechanisms then include the promotion of inflammation and oxidative stress.
There is no evidence that HCV encodes its own miRNAs. This is probable because of the separation of the first step of the miRNA biogenesis in the nucleus and replication of the RNA viruses in the cytoplasm where they are physically separated from the nuclear Drosha enzyme and thus cannot undergo the splicing process to generate pre-miRNAs. Still, some groups searched for HCV-encoded miRNAs, but with no success [155]. Nevertheless, HCV infection is associated with changes in cellular miRNA expression, and also, cellular miRNAs influence the HCV life cycle.
An important role in HCV infection and life cycle is played by liver-specific cellular miR-122, whose downregulation results in a decrease in the HCV RNA level [156,157,158]. This miRNA has a binding site in the 5′ UTR of the HCV genome and, interestingly, its binding to the target site does not lead to the repression of HCV genes, but miR-122 protects the HCV genome from nucleolytic degradation and, in this way, promotes viral RNA stability. This miRNA is a very promising candidate for the anti-HCV treatment. Its inhibition by antisense oligonucleotides has been tested in animals [159], and it is now in clinical trials for the treatment of HCV infection [160]. Apart from miR-122, other miRNAs were found to inhibit HCV replication and therefore are potential targets for anti-HCV therapy. MiR-199a targets the 5′ UTR of the HCV genome [161] and appears to be decreased in HCC [162]. MiRNA let-7b binds to two conserved regions in the HCV genome, 5′ UTR and NS5B and besides the inhibition of viral replication, it acts synergistically with IFNα [163]. Mukherjee et al. [164] have shown that miR-181c binds to the E1 and NS5A sites in the HCV genome and reduces viral replication. However, still more research is needed, since the efficiency of miR-181c binding differs between HCV genotypes. The HCV life cycle can also be regulated by host miRNAs that target host mRNA. MiR-373 facilitates HCV RNA replication through the regulation of the JAK/STAT signaling pathway [165], and miR-27a influences the production of HCV particles by inhibiting genes related to the lipid metabolism signaling pathways [166].
There are many studies reporting deregulated expression of cellular miRNAs in HCV-associated tumors. Zhang et al. [167] have observed the upregulation of miR-155 during HCV infection. This miRNA promotes the proliferation of hepatocytes by the activation of Wnt signaling and inhibits apoptosis. Moreover, the growth, proliferation and tumorigenesis of hepatocytes are facilitated by the downregulation of miR-152 [168], miR-181c [164], or miR-491 [169]. The direct role of miR-141 has been shown by Banaudha et al. [170], who found miR-141, required for HCV replication, to inhibit tumor suppressor gene DCL-1 (Dicer-like 1) which encodes a Rho GTPase-activating protein, and thus promotes the cell proliferation. Varnholt et al. [171] have examined the miRNA expression profiles in a set of liver tumors and dysplastic samples. They have revealed 10 upregulated and 19 downregulated miRNAs in tumors compared to normal tissues. Moreover, they validated five of these miRNAs on a larger set of samples and found the well-known miR-122 to be overexpressed, as was also the case with miR-100 and miR-10a, whereas the expression of miR-198 and miR-145, considered as tumor suppressors, was significantly decreased in tumors. Ura et al. [172] performed a study comparing miRNAs in HBV- and HCV-associated HCC and have revealed that in HCV-related HCC, the differentially deregulated miRNAs are linked to the regulation of the immune response, antigen presentation, cell cycle, or lipid metabolism, while in HBV-associated HCC, they are rather involved in the pathways regulating cell death, DNA damage or signal transduction. Bandiera et al. [173] performed a profiling analysis and have revealed 72 miRNAs to be deregulated more than two-fold in HCC. They further focused on miR-146a-5p, which positively influences the HCV replication and increases HCV infection. Finally, a comprehensive study was done by Pineau et al. [174], who analyzed 104 HCC cases, 90 cirrhotic livers, 21 normal tissues and 35 HCC cell lines, and have identified 12 miRNAs (miR-106b, miR-21, miR-210, miR-221, miR-222, miR-224, miR-34a, miR-425, miR-519a, miR-93, miR-96 and let-7c) as linked to disease progression and tumorigenesis, with four of them (miR-21, miR-221, miR-222 and miR-224) being previously reported as deregulated in HCC.

8. Retroviruses

Retroviruses are a group of single-stranded RNA viruses that use their own encoded reverse transcriptase to produce DNA intermediate from their RNA genome, and then the virus integrates into the genome of the host and is transcribed and translated along the cellular genes. Retroviruses include tumor-associated viruses infecting animals, such as Rous sarcoma virus or mouse mammary tumor virus (MMTV). The malignant transformation is caused by viral proto-oncogenes or through the disruption or activation of cellular proto-oncogenes. The most important tumorigenic retrovirus of humans is human T-cell lymphotropic virus 1 (HTLV-1) from the genus Deltavirus, which is linked to the type of lymphocytic leukemia and non-Hodgkin lymphoma called adult T-cell leukemia/lymphoma (ATL). HTLV-1 was responsible for only 0.1% of new cancer cases attributable to infectious agents in 2012, with around 3000 new cases reported worldwide [1]. HTLV-1 encodes the oncogenic protein Tax, which interacts with more than one hundred cellular proteins and prevents apoptosis, enhances cell signaling, induces cell cycle dysregulation, or activates cellular proto-oncogenes. The second important oncogenic protein is HTLV-1 bZIP factor (HBZ), which is present in 100% of ATL cells, enhances T-cell proliferation, and contributes to the prevention of apoptosis [175]. The human immunodeficiency virus (HIV), a member of the genus Lentivirus, causes acquired immune deficiency syndrome (AIDS). This virus does not appear to induce cancer directly, but increases the risk of the development of other viruses-related tumors, such as Kaposi’s sarcoma, cervical cancer, or non-Hodgkin lymphoma.
There are several studies focused on cellular miRNA targets in the retroviral genome and the influence of their binding on viral replication, gene expression, or infectivity. Huang et al. [176] have shown that the 3′ end of the HIV mRNA in resting CD4+ T-cells is targeted by cellular miR-28, miR-125b, miR-150, miR-223 or miR-382, and contributes to HIV-1 latency. Two computational studies were conducted to find potential target sites of cellular miRNAs in HTLV-1 [177,178]. Bai and Nicot [179] have found that miR-28-3p inhibits HTLV-1 replication and expression by targeting a specific site within gag/pol in viral mRNA, and have identified a mechanism of how cellular miRNA prevents viral transmission. Besides the direct targeting of the viral genome, viral replication can also be influenced by cellular miRNAs indirectly through host-dependency factors (HDFs) [180]. For example, miR-20a and miR-17-5p target the p300/CBP-associated factor important for long terminal repeat (LTR) activation, and the upregulation of these miRNAs reduces HIV-1 replication [181]. Further, the overexpression of miR-198 and miR-27b leads to the repression of cyclin-T1, a cofactor of Tat, and thus to HIV inhibition [182,183]. On the other hand, miR-217 and miR-34a target sirtuin 1 (SIRT1), which disrupts LTR activation by Tat, leading to HIV transactivation [184].
Similarly to other oncoviruses, retroviruses also dysregulate the expression of cellular miRNAs. Van Duyne et al. [185] have shown that HTLV-1 infection significantly downregulates Drosha protein expression, which is required for the cleavage of pri-miRNA, by direct interaction with the Tax protein, and thus deregulates the miRNA biogenesis pathway. Several studies have characterized the miRNA expression profiles in HTLV-1-transformed cell lines or ATL patients. Pichler et al. [186] have demonstrated deregulation of five miRNAs (miR-21, miR-24, miR-146a, miR-155 and miR-223) in HTLV-1-transformed T-cells. Moreover, they have found that miR-146a is transactivated directly by the Tax protein via NF-κB signaling, and its upregulation promotes HTLV-1 T-cell proliferation. The analysis of miRNA expression of HTLV-1 transformed T-cell lines and ATL patients has revealed six miRNAs to be consistently upregulated, with two of them (miR-93 and miR-130b) targeting the 3′ UTR of tumor suppressor protein TP53INP1 (TP53-induced nuclear protein 1), impacting proliferation and survival of HTLV-1-transformed/infected cells [187]. Bellon et al. [188] analyzed the miRNA profiles of ATL patients with microarrays, reporting deregulation of several miRNAs. However, they have also observed that two miRNAs (miR-150 and miR-223) are differentially expressed, both in vitro and ex vivo. Similarly, Yamagishi et al. [189] performed microarray analysis of ATL cells from patients and, interestingly, have revealed downregulation of 59 miRNAs out of 61, with miR-31 being the most repressed. MiR-31 is reported as a tumor suppressor regulating the NF-κB signaling pathway, and its deregulation leads to resistance of cells to apoptosis. The cellular miRNA expression can also be influenced by another retroviral oncoprotein, HBZ, which activates miR-17 and miR-21 in CD4+ T-cells [190]. These miRNAs target DNA-damage factor OBFC2A and thus promote cell proliferation and genomic instability.

9. Controversial Oncoviral-Encoded miRNAs

Besides approved and validated oncoviral-encoded miRNAs, the existence of viral-specific miRNAs from other groups of human oncoviruses has been reported in the literature. However, for these miRNAs, the evidence of their miRNA biogenesis as well as their function and clinical significance is not in the literature adequately supported. Therefore, further research is needed.
The existence of HBV-encoded miRNAs was not experimentally confirmed until recently. There was only one study, that of Jin et al. [191], who analyzed candidates for viral-encoded miRNAs in silico. They found only one pre-miRNA candidate for which one target viral mRNA was revealed but was not confirmed in vivo. No cellular mRNA was found as a target of this predicted viral miRNA. Recently, Yang et al. [192] performed a study of HBV-encoded miRNAs by deep sequencing and Northern blotting. Although they did not find the previously computationally predicted miRNA [191], they identified five small noncoding RNAs (snRNAs) aligning to HBV transcripts, and validated a novel HBV-miR-3, which they suggested, is involved in the viral replication process and represses HBV protein expression and virion production, probably contributing to the establishment of persistent infection. However, the number of reads obtained by deep sequencing in their study is not compelling, since it makes up only <0.0004% of the standard number of NGS reads. Moreover, the predicted secondary structure of pre-miRNA also does not fulfil the criteria for authentic viral miRNAs and natural substrate for enzymes of miRNAs biogenesis. Furthermore, they showed that the biogenesis of this HBV-encoded snRNA proceeds via the classical Dicer and Drosha route [192]. This is contradictory to results published by Wang et al. [193], who demonstrated that HBV-derived snRNAs are not processed by Dicer. Additionally, several studies analyzed the expression of snRNAs in hepatocellular carcinomas associated with HBV by deep sequencing [162,194,195,196]. Even though these studies were focused primarily on cellular miRNAs, we assume that any HBV viral miRNAs markedly differentially expressed would have been noticed in these studies. Thus, these controversial data highlight the fact that further research on HBV-encoded miRNAs is needed.
The second group of oncoviruses with not-definitely-approved viral-encoded miRNAs are HPVs. It is generally accepted that HPVs do not encode their own miRNAs; nevertheless, results of two research groups have suggested the existence of HPV-encoded miRNAs. First, the group of Auvinen has reported the identification and validation of the first papillomavirus-encoded miRNAs in human cervical lesions and in cell lines using SOLiD sequencing, quantitative RT–PCR, and in-situ hybridization [197]. They have successfully validated four miRNAs, and based on the prediction of target genes, they have suggested their role in cell cycle regulation, immune functions, cell adhesion and migration, development, and cancer. Several years later, the same group performed the analysis of the reported miRNAs in cervical samples by quantitative RT–PCR, and they detected low levels of expression of these miRNAs in all cases [198]. Finally, Weng et al. [199] have developed a systematic method for viral miRNA identification and regulatory network construction based on genome-wide sequence analysis, and have predicted other putative miRNAs by bioinformatics approaches. The target genes of these predicted miRNAs play roles in virus infection and carcinogenesis and might be possible targets for antiviral drugs. However, no studies of in-vivo function of the predicted HPV-specific miRNAs have been published so far.
The topic of miRNAs encoded by retroviruses is also still quite controversial. One of the reasons is the risk of cleavage of the viral RNA genome with Rnase Drosha during the biogenesis of miRNAs. However, two groups have reported studies of in-vitro Dicer processing of ~50-nt long HIV-1 TAR RNA, which forms a stem–loop structure similar to pre-miRNA [200,201]. Moreover, Rouha et al. [202] have revealed that miRNAs might be produced by RNA viruses replicating in the cytoplasm without impairing viral RNA replication. Recently, Harwig et al. [203] suggested that the HIV-1 TAR hairpin structure could be a source of miRNAs without cleavage of the RNA genome, however, the biogenesis differ from the canonical miRNA pathway. Currently, the miRNA database (available online: http://mirbase.org) indicates that HIV-1 encodes three precursors of miRNAs and four mature miRNAs, however, they should be referred to as small noncoding RNAs (snRNAs) since there is a lack of significant experimental support demonstrating that these are functional miRNAs that arise from a stable hairpin RNA structure and are processed by the classical miRNA biogenesis pathway. Bernard et al. [204] have reported that HIV-1 produces the viral miRNAs vmiR-88, vmiR-99 and vmiR-TAR, with the first two stimulating human macrophage TNFα release and contributing to chronic immune activation; however, in-vivo confirmation of their in-vitro results remains to be determined. Moreover, Li et al. [205] have detected vmiR-TAR-3p in primary macrophages infected by HIV, and have shown its inhibitory effect on the viral replication. Klase et al. [206] and Ouellet et al. [207] have reported the anti-apoptotic role of vmiR-TAR-5p and vmiR-TAR-3p. Further, hiv1-miR-N367, described within the nef gene, targets the Nef protein for degradation, which may play a role in the establishment of viral latency [208,209]. Finally, hiv1-miR-H1, identified in 3′ LTR, targets the gene for apoptosis antagonizing transcription factor (AATF), leading to an increase in cell apoptosis [210], and hiv1-miR-H3 has been reported to target 5′ LTR within the TATA box increasing the promoter activity and positively regulating the viral replication [211]. Unlike for HIV, miRNAs encoded by HTLV-1 have not yet been identified. Despite these findings, various reports have been published where the authors failed to detect HIV-1 miRNAs, and/or the candidate miRNAs failed to satisfy all defined criteria for authentic viral miRNAs [155,212,213]. Lin et al. [212] demonstrated that neither HIV-1 nor HTLV-1 express significant levels of small interfering RNAs (siRNAs) or miRNAs, as well as that they do not repress cellular RNA interference machinery in the infected cells. This was supported by Whisnant et al. [213], who performed deep sequencing analysis of HIV-1 infected cell cultures and revealed only very few reads aligning to the viral genome. In contrast to reads aligning to the human genome that peak at ~22 nt, viral reads showed more reads at smaller size. Moreover, matching of HIV-1-derived snRNAs to the proviral genome was scattered over the proviral sequence, and their 5′ ends did not share the parameters characteristic for the authentic miRNAs. The authors also refuted the TAR-derived miRNAs that are mentioned above [206,207], since the TAR stem–loop differs from the authentic pre-miRNAs. Finally, they demonstrated [213] that HIV-1-derived snRNAs were not loaded into RNA-induced silencing complex (RISC), and further, they failed to detect a significant level of small RNA reads derived from the HIV-1 antisense strand, which was previously reported by Schopman et al. [214]. Similarly, Vongrad et al. [215], using high-throughput methods, failed to detect the incorporation of HIV-1-derived sncRNA or HIV-1 target sequences into the AGO2-RISC complex of RNAi pathway. However, it is worth mentioning the observation made by Kincaid et al. [216], who found out that bovine leukemia virus (BLV) from the family Retroviridae encodes a conserved cluster of miRNAs. They further show that one of these viral miRNAs shares a partial sequence with cellular miR-29, whose overexpression is associated with B-cell neoplasm. This type of malignancy resembles tumors initiated by BLV, and therefore, their findings suggest the possible way how this BLV-associated miRNA can contribute to tumorigenesis. Therefore, despite the numerous studies that support the nonexistence of HIV-1-specific miRNAs, the findings of bovine leukemia virus-specific miRNAs pointed to the importance of further research in this area.

10. Concluding Remarks

Carcinogenic infections are the cause of 15% of tumors worldwide. Tumors related to oncoviruses are studied extensively with the aim to detect new diagnostic and prognostic markers and treatment targets. This review provides a comprehensive overview on the mechanisms of the contribution of human oncoviruses to tumor development, and describes how oncoviruses utilize their own encoded sequences, miRNAs, for the regulation of their gene expression, as well as to influence the gene expression of their hosts (summarized in Table 1 and Figure 1). Besides the expression and function of miRNAs encoded by some groups of oncoviruses, the existence of virally coded miRNAs in several groups of human oncoviruses remains controversial. However, the miRNA regulation is reciprocal and the viral life cycle can also be influenced by cellular miRNAs. In this review, we summarize the accumulated body of knowledge in this area and focus on the oncogenesis mediated by EBV, HHV-8, HBV, HPV, MCPyV, HCV, HIV and HTLV-1. The research into miRNA profiling to set a panel of diagnostic miRNAs for specific tumors is of high relevance, and there have been already developed cancer focus panels with differentially expressed miRNAs for breast cancer, prostate cancer or lung cancer. MiRNAs could be a promising tool for early diagnosis of virus-related tumors and their noninvasive treatment. Currently, some miRNA-based therapies are being tested in preclinical and clinical trials, for example, miR-122 in HCV infection, miR-34 in liver cancer, or miR-208 in cardiometabolic disease [217]. Despite these achievements, additional research is needed for a more precise understanding of the miRNA pathways, including those that are virus associated.

Acknowledgments

The authors thank Lucie Dvorakova for help with literature search, Martina Salakova. For critical reading and Ruth Tachezy Jr. for the help with graphical abstract. The paper was supported by the Ministry of Education, Youth and Sports of the Czech Republic (Available online: http://www.msmt.cz/) within the National Sustainability Program II (BIOCEV-FAR project) LQ1604 and by the project BIOCEV (CZ.1.05/1.1.00/02.0109).

Author Contributions

Zuzana Vojtechova and Ruth Tachezy made the conceptualization of the manuscript; Ruth Tachezy was responsible for the funding acquisition; Zuzana Vojtechova wrote the original draft of the manuscript; Ruth Tachezy made the figure and concept of the graphical abstract; Zuzana Vojtechova and Ruth Tachezy wrote, reviewed and edited the final version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Glossary

Immortalization of the host cellcontinual proliferation of the cell mostly caused by mutation or by the activity of the viral oncogenes
Transformation of the host cellmorphologic, physiologic and genetic changes of the cell initiating a process of tumor development and progression

References

  1. Plummer, M.; de Martel, C.; Vignat, J.; Ferlay, J.; Bray, F.; Franceschi, S. Global burdenf cancers attributable tonfectionsn 2012: A synthetic analysis. Lancet Glob. Health 2016, 4, e609–e616. [Google Scholar] [CrossRef]
  2. Hanahan, D.; Weinberg, R.A. The hallmarksf cancer. Cell 2000, 100, 57–70. [Google Scholar] [CrossRef]
  3. Hanahan, D.; Weinberg, R.A. Hallmarksf cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed]
  4. Bouvard, V.; Baan, R.; Straif, K.; Grosse, Y.; Secretan, B.; El Ghissassi, F.; Benbrahim-Tallaa, L.; Guha, N.; Freeman, C.; Galichet, L.; et al. A reviewf human carcinogens—Part B: Biological agents. Lancet Oncol. 2009, 10, 321–322. [Google Scholar] [CrossRef]
  5. Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297. [Google Scholar] [CrossRef]
  6. Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120, 15–20. [Google Scholar] [CrossRef] [PubMed]
  7. Lu, J.; Getz, G.; Miska, E.A.; Alvarez-Saavedra, E.; Lamb, J.; Peck, D.; Sweet-Cordero, A.; Ebert, B.L.; Mak, R.H.; Ferrando, A.A.; et al. MicroRNA expression profiles classify human cancers. Nature 2005, 435, 834–838. [Google Scholar] [CrossRef] [PubMed]
  8. Anastasiadou, E.; Jacob, L.S.; Slack, F.J. Non-coding RNA networksn cancer. Nat. Rev. Cancer 2018, 18, 5–18. [Google Scholar] [CrossRef] [PubMed]
  9. Cullen, B.R. Viruses and microRNAs: RISCynteractions with serious consequences. Genes Dev. 2011, 25, 1881–1894. [Google Scholar] [CrossRef] [PubMed]
  10. Epstein, M.A.; Achong, B.G.; Barr, Y.M. Virus Particlesn Cultured Lymphoblasts from Burkitt’s Lymphoma. Lancet 1964, 1, 702–703. [Google Scholar] [CrossRef]
  11. Mui, U.N.; Haley, C.T.; Tyring, S.K. Viral Oncology: Molecular Biology and Pathogenesis. J. Clin. Med. 2017, 6. [Google Scholar] [CrossRef] [PubMed]
  12. Pavlovic, A.; Glavina Durdov, M.; Capkun, V.; Jakelic Pitesa, J.; Bozic Sakic, M. Classical Hodgkin Lymphoma with Positive Epstein-Barr Virus Statuss Associated with More FOXP3 Regulatory T Cells. Med. Sci. Monit. 2016, 22, 2340–2346. [Google Scholar] [CrossRef] [PubMed]
  13. Carbone, A.; Gloghini, A.; Dotti, G. EBV-associated lymphoproliferativeisorders: Classification and treatment. Oncologist 2008, 13, 577–585. [Google Scholar] [CrossRef] [PubMed]
  14. Jacome, A.A.; Lima, E.M.; Kazzi, A.I.; Chaves, G.F.; Mendonca, D.C.; Maciel, M.M.; Santos, J.S. Epstein-Barr virus-positive gastric cancer: Aistinct molecular subtypef theisease? Rev. Soc. Bras. Med. Trop. 2016, 49, 150–157. [Google Scholar] [CrossRef] [PubMed]
  15. Cai, Q.; Chen, K.; Young, K.H. Epstein-Barr virus-positive T/NK-cell lymphoproliferativeisorders. Exp. Mol. Med. 2015, 47, e133. [Google Scholar] [CrossRef] [PubMed]
  16. Mancao, C.; Hammerschmidt, W. Epstein-Barr virus latent membrane protein 2As a B-cell receptor mimic and essential for B-cell survival. Blood 2007, 110, 3715–3721. [Google Scholar] [CrossRef] [PubMed]
  17. Swanson-Mungerson, M.; Bultema, R.; Longnecker, R. Epstein-Barr virus LMP2Amposes sensitivity to apoptosis. J. Gen. Virol. 2010, 91, 2197–2202. [Google Scholar] [CrossRef] [PubMed]
  18. Incrocci, R.; Barse, L.; Stone, A.; Vagvala, S.; Montesano, M.; Subramaniam, V.; Swanson-Mungerson, M. Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 production through the activationf Bruton’s tyrosine kinase and STAT3. Virology 2017, 500, 96–102. [Google Scholar] [CrossRef] [PubMed]
  19. Sivachandran, N.; Wang, X.; Frappier, L. Functionsf the Epstein-Barr virus EBNA1 proteinn viral reactivation and lyticnfection. J. Virol. 2012, 86, 6146–6158. [Google Scholar] [CrossRef] [PubMed]
  20. Sivachandran, N.; Sarkari, F.; Frappier, L. Epstein-Barr nuclear antigen 1 contributes to nasopharyngeal carcinoma throughisruptionf PML nuclear bodies. PLoS Pathog. 2008, 4, e1000170. [Google Scholar] [CrossRef] [PubMed]
  21. Kaiser, C.; Laux, G.; Eick, D.; Jochner, N.; Bornkamm, G.W.; Kempkes, B. The proto-oncogene c-mycs airect target genef Epstein-Barr virus nuclear antigen 2. J. Virol. 1999, 73, 4481–4484. [Google Scholar] [PubMed]
  22. Bhattacharjee, S.; Ghosh Roy, S.; Bose, P.; Saha, A. Rolef EBNA-3 Family Proteinsn EBV Associated B-cell Lymphomagenesis. Front. Microbiol. 2016, 7, 457. [Google Scholar] [CrossRef] [PubMed]
  23. Pfeffer, S.; Zavolan, M.; Grasser, F.A.; Chien, M.; Russo, J.J.; Ju, J.; John, B.; Enright, A.J.; Marks, D.; Sander, C.; et al. Identificationf virus-encoded microRNAs. Science 2004, 304, 734–736. [Google Scholar] [CrossRef] [PubMed]
  24. Kincaid, R.P.; Sullivan, C.S. Virus-encoded microRNAs: Anverview and a look to the future. PLoS Pathog. 2012, 8, e1003018. [Google Scholar] [CrossRef] [PubMed]
  25. Lo, A.K.; To, K.F.; Lo, K.W.; Lung, R.W.; Hui, J.W.; Liao, G.; Hayward, S.D. Modulationf LMP1 protein expression by EBV-encoded microRNAs. Proc. Natl. Acad. Sci. USA 2007, 104, 16164–16169. [Google Scholar] [CrossRef] [PubMed]
  26. Lung, R.W.; Tong, J.H.; Sung, Y.M.; Leung, P.S.; Ng, D.C.; Chau, S.L.; Chan, A.W.; Ng, E.K.; Lo, K.W.; To, K.F. Modulationf LMP2A expression by a newlydentified Epstein-Barr virus-encoded microRNA miR-BART22. Neoplasia 2009, 11, 1174–1184. [Google Scholar] [CrossRef] [PubMed]
  27. Barth, S.; Pfuhl, T.; Mamiani, A.; Ehses, C.; Roemer, K.; Kremmer, E.; Jaker, C.; Hock, J.; Meister, G.; Grasser, F.A. Epstein-Barr virus-encoded microRNA miR-BART2own-regulates the viral DNA polymerase BALF5. Nucleic Acids Res. 2008, 36, 666–675. [Google Scholar] [CrossRef] [PubMed]
  28. Iizasa, H.; Wulff, B.E.; Alla, N.R.; Maragkakis, M.; Megraw, M.; Hatzigeorgiou, A.; Iwakiri, D.; Takada, K.; Wiedmer, A.; Showe, L.; et al. Editingf Epstein-Barr virus-encoded BART6 microRNAs controls theiricer targeting and consequently affects viral latency. J. Biol. Chem. 2010, 285, 33358–33370. [Google Scholar] [CrossRef] [PubMed]
  29. Choy, E.Y.; Siu, K.L.; Kok, K.H.; Lung, R.W.; Tsang, C.M.; To, K.F.; Kwong, D.L.; Tsao, S.W.; Jin, D.Y. An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J. Exp. Med. 2008, 205, 2551–2560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Cai, L.M.; Lyu, X.M.; Luo, W.R.; Cui, X.F.; Ye, Y.F.; Yuan, C.C.; Peng, Q.X.; Wu, D.H.; Liu, T.F.; Wang, E.; et al. EBV-miR-BART7-3p promotes the EMT and metastasisf nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN. Oncogene 2015, 34, 2156–2166. [Google Scholar] [CrossRef] [PubMed]
  31. Vereide, D.T.; Seto, E.; Chiu, Y.F.; Hayes, M.; Tagawa, T.; Grundhoff, A.; Hammerschmidt, W.; Sugden, B. Epstein-Barr virus maintains lymphomas viats miRNAs. Oncogene 2014, 33, 1258–1264. [Google Scholar] [CrossRef] [PubMed]
  32. Lei, T.; Yuen, K.S.; Tsao, S.W.; Chen, H.; Kok, K.H.; Jin, D.Y. Perturbationf biogenesis and targetingf Epstein-Barr virus-encoded miR-BART3 microRNA by adenosine-to-inosine editing. J. Gen. Virol. 2013, 94, 2739–2744. [Google Scholar] [CrossRef] [PubMed]
  33. Xia, T.; O’Hara, A.; Araujo, I.; Barreto, J.; Carvalho, E.; Sapucaia, J.B.; Ramos, J.C.; Luz, E.; Pedroso, C.; Manrique, M.; et al. EBV microRNAsn primary lymphomas and targetingf CXCL-11 by ebv-mir-BHRF1-3. Cancer Res. 2008, 68, 1436–1442. [Google Scholar] [CrossRef] [PubMed]
  34. Feederle, R.; Haar, J.; Bernhardt, K.; Linnstaedt, S.D.; Bannert, H.; Lips, H.; Cullen, B.R.; Delecluse, H.J. The membersf an Epstein-Barr virus microRNA cluster cooperate to transform B lymphocytes. J. Virol. 2011, 85, 9801–9810. [Google Scholar] [CrossRef] [PubMed]
  35. Wahl, A.; Linnstaedt, S.D.; Esoda, C.; Krisko, J.F.; Martinez-Torres, F.; Delecluse, H.J.; Cullen, B.R.; Garcia, J.V. A clusterf virus-encoded microRNAs accelerates acute systemic Epstein-Barr virusnfection butoes not significantly enhance virus-inducedncogenesisn vivo. J. Virol. 2013, 87, 5437–5446. [Google Scholar] [CrossRef] [PubMed]
  36. Nachmani, D.; Stern-Ginossar, N.; Sarid, R.; Mandelboim, O. Diverse herpesvirus microRNAs target the stress-inducedmmune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe 2009, 5, 376–385. [Google Scholar] [CrossRef] [PubMed]
  37. Kang, B.W.; Choi, Y.; Kwon, O.K.; Lee, S.S.; Chung, H.Y.; Yu, W.; Bae, H.I.; Seo, A.N.; Kang, H.; Lee, S.K.; et al. High levelf viral microRNA-BART20-5p expressions associated with worse survivalf patients with Epstein-Barr virus-associated gastric cancer. Oncotarget 2017, 8, 14988–14994. [Google Scholar] [CrossRef] [PubMed]
  38. Gao, W.; Li, Z.H.; Chen, S.; Chan, J.Y.; Yin, M.; Zhang, M.J.; Wong, T.S. Epstein-Barr virus encoded microRNA BART7 regulates radiation sensitivityf nasopharyngeal carcinoma. Oncotarget 2017, 8, 20297–20308. [Google Scholar] [CrossRef] [PubMed]
  39. Godshalk, S.E.; Bhaduri-McIntosh, S.; Slack, F.J. Epstein-Barr virus-mediatedysregulationf human microRNA expression. Cell Cycle 2008, 7, 3595–3600. [Google Scholar] [CrossRef] [PubMed]
  40. Cheung, C.C.; Chung, G.T.; Lun, S.W.; To, K.F.; Choy, K.W.; Lau, K.M.; Siu, S.P.; Guan, X.Y.; Ngan, R.K.; Yip, T.T.; et al. miR-31s consistentlynactivatedn EBV-associated nasopharyngeal carcinoma and contributes tots tumorigenesis. Mol. Cancer 2014, 13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Zhu, X.; Wang, Y.; Sun, Y.; Zheng, J.; Zhu, D. MiR-155 up-regulation by LMP1 DNA contributes toncreased nasopharyngeal carcinoma cell proliferation and migration. Eur. Arch. Otorhinolaryngol. 2014, 271, 1939–1945. [Google Scholar] [CrossRef] [PubMed]
  42. Linnstaedt, S.D.; Gottwein, E.; Skalsky, R.L.; Luftig, M.A.; Cullen, B.R. Virallynduced cellular microRNA miR-155 plays a key rolen B-cellmmortalization by Epstein-Barr virus. J. Virol. 2010, 84, 11670–11678. [Google Scholar] [CrossRef] [PubMed]
  43. Yang, F.; Liu, Q.; Hu, C.M. Epstein-Barr virus-encoded LMP1ncreases miR-155 expression, which promotes radioresistancef nasopharyngeal carcinoma via suppressing UBQLN1. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 4507–4515. [Google Scholar] [PubMed]
  44. Du, Z.M.; Hu, L.F.; Wang, H.Y.; Yan, L.X.; Zeng, Y.X.; Shao, J.Y.; Ernberg, I. Upregulationf MiR-155n nasopharyngeal carcinomas partlyriven by LMP1 and LMP2A andownregulates a negative prognostic marker JMJD1A. PLoS ONE 2011, 6, e19137. [Google Scholar] [CrossRef] [PubMed]
  45. Sakamoto, K.; Sekizuka, T.; Uehara, T.; Hishima, T.; Mine, S.; Fukumoto, H.; Sato, Y.; Hasegawa, H.; Kuroda, M.; Katano, H. Next-generation sequencingf miRNAsn clinical samplesf Epstein-Barr virus-associated B-cell lymphomas. Cancer Med. 2017, 6, 605–618. [Google Scholar] [CrossRef] [PubMed]
  46. Leucci, E.; Onnis, A.; Cocco, M.; De Falco, G.; Imperatore, F.; Giuseppina, A.; Costanzo, V.; Cerino, G.; Mannucci, S.; Cantisani, R.; et al. B-cellifferentiationn EBV-positive Burkitt lymphomasmpaired at posttranscriptional level by miRNA-altered expression. Int. J. Cancer 2010, 126, 1316–1326. [Google Scholar] [CrossRef] [PubMed]
  47. Rosato, P.; Anastasiadou, E.; Garg, N.; Lenze, D.; Boccellato, F.; Vincenti, S.; Severa, M.; Coccia, E.M.; Bigi, R.; Cirone, M.; et al. Differential regulationf miR-21 and miR-146a by Epstein-Barr virus-encoded EBNA2. Leukemia 2012, 26, 2343–2352. [Google Scholar] [CrossRef] [PubMed]
  48. Oussaief, L.; Fendri, A.; Chane-Woon-Ming, B.; Poirey, R.; Delecluse, H.J.; Joab, I.; Pfeffer, S. Modulationf MicroRNA Cluster miR-183-96-182 Expression by Epstein-Barr Virus Latent Membrane Protein 1. J. Virol. 2015, 89, 12178–12188. [Google Scholar] [CrossRef] [PubMed]
  49. Chen, X.; Shi, J.; Zhong, J.; Huang, Z.; Luo, X.; Huang, Y.; Feng, S.; Shao, J.; Liu, D. miR-1, regulated by LMP1, suppresses tumour growth and metastasis by targeting K-rasn nasopharyngeal carcinoma. Int. J. Exp. Pathol. 2015, 96, 427–432. [Google Scholar] [CrossRef] [PubMed]
  50. Chang, Y.; Cesarman, E.; Pessin, M.S.; Lee, F.; Culpepper, J.; Knowles, D.M.; Moore, P.S. Identificationf herpesvirus-like DNA sequencesn AIDS-associated Kaposi’s sarcoma. Science 1994, 266, 1865–1869. [Google Scholar] [CrossRef] [PubMed]
  51. Nador, R.G.; Cesarman, E.; Chadburn, A.; Dawson, D.B.; Ansari, M.Q.; Sald, J.; Knowles, D.M. Primary effusion lymphoma: Aistinct clinicopathologic entity associated with the Kaposi’s sarcoma-associated herpes virus. Blood 1996, 88, 645–656. [Google Scholar] [PubMed]
  52. Soulier, J.; Grollet, L.; Oksenhendler, E.; Cacoub, P.; Cazals-Hatem, D.; Babinet, P.; Agay, M.F.; Clauvel, J.P.; Raphael, M.; Degos, L. Kaposi’s sarcoma-associated herpesvirus-like DNA sequencesn multicentric Castleman’s disease. Blood 1995, 86, 1276–1280. [Google Scholar] [PubMed]
  53. Cai, X.; Lu, S.; Zhang, Z.; Gonzalez, C.M.; Damania, B.; Cullen, B.R. Kaposi’s sarcoma-associated herpesvirus expresses an arrayf viral microRNAsn latentlynfected cells. Proc. Natl. Acad. Sci. USA 2005, 102, 5570–5575. [Google Scholar] [CrossRef] [PubMed]
  54. Bellare, P.; Ganem, D. Regulationf KSHV lytic switch protein expression by a virus-encoded microRNA: An evolutionary adaptation that fine-tunes lytic reactivation. Cell Host Microbe 2009, 6, 570–575. [Google Scholar] [CrossRef] [PubMed]
  55. Lin, X.; Liang, D.; He, Z.; Deng, Q.; Robertson, E.S.; Lan, K. miR-K12-7-5p encoded by Kaposi’s sarcoma-associated herpesvirus stabilizes the latent state by targeting viral ORF50/RTA. PLoS ONE 2011, 6, e16224. [Google Scholar] [CrossRef] [PubMed]
  56. Lu, C.C.; Li, Z.; Chu, C.Y.; Feng, J.; Feng, J.; Sun, R.; Rana, T.M. MicroRNAs encoded by Kaposi’s sarcoma-associated herpesvirus regulate viral life cycle. EMBO Rep. 2010, 11, 784–790. [Google Scholar] [CrossRef] [PubMed]
  57. Li, W.; Jia, X.; Shen, C.; Zhang, M.; Xu, J.; Shang, Y.; Zhu, K.; Hu, M.; Yan, Q.; Qin, D.; et al. A KSHV microRNA enhances viral latency andnduces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway. Oncotarget 2016, 7, 32286–32305. [Google Scholar] [CrossRef] [PubMed]
  58. Plaisance-Bonstaff, K.; Choi, H.S.; Beals, T.; Krueger, B.J.; Boss, I.W.; Gay, L.A.; Haecker, I.; Hu, J.; Renne, R. KSHV miRNAsecrease expressionf lytic genesn latentlynfected PEL and endothelial cells by targeting host transcription factors. Viruses 2014, 6, 4005–4023. [Google Scholar] [CrossRef] [PubMed]
  59. Lacoste, V.; Nicot, C.; Gessain, A.; Valensi, F.; Gabarre, J.; Matta, H.; Chaudhary, P.M.; Mahieux, R. In primary effusion lymphoma cells, MYB transcriptional repressions associated with v-FLIP expressionuring latent KSHVnfection while both v-FLIP and v-GPCR becomenvolveduring the lytic cycle. Br. J. Haematol. 2007, 138, 487–501. [Google Scholar] [CrossRef] [PubMed]
  60. Liang, D.; Gao, Y.; Lin, X.; He, Z.; Zhao, Q.; Deng, Q.; Lan, K. A human herpesvirus miRNA attenuatesnterferon signaling and contributes to maintenancef viral latency by targeting IKKepsilon. Cell Res. 2011, 21, 793–806. [Google Scholar] [CrossRef] [PubMed]
  61. Lu, F.; Stedman, W.; Yousef, M.; Renne, R.; Lieberman, P.M. Epigenetic regulationf Kaposi’s sarcoma-associated herpesvirus latency by virus-encoded microRNAs that target Rta and the cellular Rbl2-DNMT pathway. J. Virol. 2010, 84, 2697–2706. [Google Scholar] [CrossRef] [PubMed]
  62. Samols, M.A.; Skalsky, R.L.; Maldonado, A.M.; Riva, A.; Lopez, M.C.; Baker, H.V.; Renne, R. Identificationf cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog. 2007, 3, e65. [Google Scholar] [CrossRef] [PubMed]
  63. Li, W.; Yan, Q.; Ding, X.; Shen, C.; Hu, M.; Zhu, Y.; Qin, D.; Lu, H.; Krueger, B.J.; Renne, R.; et al. The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA. PLoS Pathog. 2016, 12, e1005605. [Google Scholar] [CrossRef] [PubMed]
  64. Guo, Y.; Li, W.; Qin, J.; Lu, C.; Fan, W. Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded microRNAs promote matrix metalloproteinases (MMPs) expression and pro-angiogenic cytokine secretionn endothelial cells. J. Med. Virol. 2017, 89, 1274–1280. [Google Scholar] [CrossRef] [PubMed]
  65. Zhu, Y.; Ramosa Silva, S.; He, M.; Liang, Q.; Lu, C.; Feng, P.; Jung, J.U.; Gao, S.J. An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis. PLoS Pathog. 2016, 12, e1005648. [Google Scholar] [CrossRef] [PubMed]
  66. Gottwein, E.; Cullen, B.R. A human herpesvirus microRNAnhibits p21 expression and attenuates p21-mediated cell cycle arrest. J. Virol. 2010, 84, 5229–5237. [Google Scholar] [CrossRef] [PubMed]
  67. Suffert, G.; Malterer, G.; Hausser, J.; Viiliainen, J.; Fender, A.; Contrant, M.; Ivacevic, T.; Benes, V.; Gros, F.; Voinnet, O.; et al. Kaposi’s sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis. PLoS Pathog. 2011, 7, e1002405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Skalsky, R.L.; Samols, M.A.; Plaisance, K.B.; Boss, I.W.; Riva, A.; Lopez, M.C.; Baker, H.V.; Renne, R. Kaposi’s sarcoma-associated herpesvirus encodes anrthologf miR-155. J. Virol. 2007, 81, 12836–12845. [Google Scholar] [CrossRef] [PubMed]
  69. Gottwein, E.; Mukherjee, N.; Sachse, C.; Frenzel, C.; Majoros, W.H.; Chi, J.T.; Braich, R.; Manoharan, M.; Soutschek, J.; Ohler, U.; et al. A viral microRNA functions as anrthologuef cellular miR-155. Nature 2007, 450, 1096–1099. [Google Scholar] [CrossRef] [PubMed]
  70. Tsai, Y.H.; Wu, M.F.; Wu, Y.H.; Chang, S.J.; Lin, S.F.; Sharp, T.V.; Wang, H.W. The M type K15 proteinf Kaposi’s sarcoma-associated herpesvirus regulates microRNA expression viats SH2-binding motif tonduce cell migration andnvasion. J. Virol. 2009, 83, 622–632. [Google Scholar] [CrossRef] [PubMed]
  71. Punj, V.; Matta, H.; Schamus, S.; Tamewitz, A.; Anyang, B.; Chaudhary, P.M. Kaposi’s sarcoma-associated herpesvirus-encoded viral FLICEnhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a. Oncogene 2010, 29, 1835–1844. [Google Scholar] [CrossRef] [PubMed]
  72. Hussein, H.A.M.; Akula, S.M. Profilingf cellular microRNA responsesuring the early stagesf KSHVnfection. Arch. Virol. 2017, 162, 3293–3303. [Google Scholar] [CrossRef] [PubMed]
  73. Marcucci, F.; Spada, E.; Mele, A.; Caserta, C.A.; Pulsoni, A. The associationf hepatitis B virusnfection with B-cell non-Hodgkin lymphoma—A review. Am. J. Blood Res. 2012, 2, 18–28. [Google Scholar] [PubMed]
  74. Ye, Y.F.; Xiang, Y.Q.; Fang, F.; Gao, R.; Zhang, L.F.; Xie, S.H.; Liu, Z.; Du, J.L.; Chen, S.H.; Hong, M.H.; et al. Hepatitis B virusnfection and riskf nasopharyngeal carcinoman southern China. Cancer Epidemiol. Biomark. Prev. 2015, 24, 1766–1773. [Google Scholar] [CrossRef] [PubMed]
  75. Ghosh, A.; Ghosh, S.; Dasgupta, D.; Ghosh, A.; Datta, S.; Sikdar, N.; Datta, S.; Chowdhury, A.; Banerjee, S. Hepatitis B Virus X Protein Upregulates hELG1/ ATAD5 Expression through E2F1n Hepatocellular Carcinoma. Int. J. Biol. Sci. 2016, 12, 30–41. [Google Scholar] [CrossRef] [PubMed]
  76. Geng, M.; Xin, X.; Bi, L.Q.; Zhou, L.T.; Liu, X.H. Molecular mechanismf hepatitis B virus X protein functionn hepatocarcinogenesis. World J. Gastroenterol. 2015, 21, 10732–10738. [Google Scholar] [CrossRef] [PubMed]
  77. Lamontagne, J.; Steel, L.F.; Bouchard, M.J. Hepatitis B virus and microRNAs: Complexnteractions affecting hepatitis B virus replication and hepatitis B virus-associatediseases. World J. Gastroenterol. 2015, 21, 7375–7399. [Google Scholar] [CrossRef] [PubMed]
  78. Pollicino, T.; Cacciola, I.; Saffioti, F.; Raimondo, G. Hepatitis B virus PreS/S gene variants: Pathobiology and clinicalmplications. J. Hepatol. 2014, 61, 408–417. [Google Scholar] [CrossRef] [PubMed]
  79. Feitelson, M.A.; Lee, J. Hepatitis B virusntegration, fragile sites, and hepatocarcinogenesis. Cancer Lett. 2007, 252, 157–170. [Google Scholar] [CrossRef] [PubMed]
  80. Lau, C.C.; Sun, T.; Ching, A.K.; He, M.; Li, J.W.; Wong, A.M.; Co, N.N.; Chan, A.W.; Li, P.S.; Lung, R.W.; et al. Viral-human chimeric transcript predisposes risk to liver cancerevelopment and progression. Cancer Cell 2014, 25, 335–349. [Google Scholar] [CrossRef] [PubMed]
  81. Levrero, M.; Zucman-Rossi, J. Mechanismsf HBV-induced hepatocellular carcinoma. J. Hepatol. 2016, 64, S84–S101. [Google Scholar] [CrossRef] [PubMed]
  82. Fan, C.G.; Wang, C.M.; Tian, C.; Wang, Y.; Li, L.; Sun, W.S.; Li, R.F.; Liu, Y.G. miR-122nhibits viral replication and cell proliferationn hepatitis B virus-related hepatocellular carcinoma and targets NDRG3. Oncol. Rep. 2011, 26, 1281–1286. [Google Scholar] [CrossRef] [PubMed]
  83. Li, C.; Wang, Y.; Wang, S.; Wu, B.; Hao, J.; Fan, H.; Ju, Y.; Ding, Y.; Chen, L.; Chu, X.; et al. Hepatitis B virus mRNA-mediated miR-122nhibition upregulates PTTG1-binding protein, which promotes hepatocellular carcinoma tumor growth and cellnvasion. J. Virol. 2013, 87, 2193–2205. [Google Scholar] [CrossRef] [PubMed]
  84. Fornari, F.; Gramantieri, L.; Giovannini, C.; Veronese, A.; Ferracin, M.; Sabbioni, S.; Calin, G.A.; Grazi, G.L.; Croce, C.M.; Tavolari, S.; et al. MiR-122/cyclin G1nteraction modulates p53 activity and affectsoxorubicin sensitivityf human hepatocarcinoma cells. Cancer Res. 2009, 69, 5761–5767. [Google Scholar] [CrossRef] [PubMed]
  85. Song, K.; Han, C.; Zhang, J.; Lu, D.; Dash, S.; Feitelson, M.; Lim, K.; Wu, T. Epigenetic regulationf MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X proteinn hepatocellular carcinoma cells. Hepatology 2013, 58, 1681–1692. [Google Scholar] [CrossRef] [PubMed]
  86. Kong, G.; Zhang, J.; Zhang, S.; Shan, C.; Ye, L.; Zhang, X. Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTENn cell culture model. PLoS ONE 2011, 6, e19518. [Google Scholar] [CrossRef] [PubMed]
  87. Wu, J.; Zhang, X.J.; Shi, K.Q.; Chen, Y.P.; Ren, Y.F.; Song, Y.J.; Li, G.; Xue, Y.F.; Fang, Y.X.; Deng, Z.J.; et al. Hepatitis B surface antigennhibits MICA and MICB expression vianductionf cellular miRNAsn hepatocellular carcinoma cells. Carcinogenesis 2014, 35, 155–163. [Google Scholar] [CrossRef] [PubMed]
  88. Wei, X.; Xiang, T.; Ren, G.; Tan, C.; Liu, R.; Xu, X.; Wu, Z. miR-101sown-regulated by the hepatitis B virus x protein andnduces aberrant DNA methylation by targeting DNA methyltransferase 3A. Cell Signal. 2013, 25, 439–446. [Google Scholar] [CrossRef] [PubMed]
  89. Huang, J.; Wang, Y.; Guo, Y.; Sun, S. Down-regulated microRNA-152nduces aberrant DNA methylationn hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology 2010, 52, 60–70. [Google Scholar] [CrossRef] [PubMed]
  90. Wei, X.; Tan, C.; Tang, C.; Ren, G.; Xiang, T.; Qiu, Z.; Liu, R.; Wu, Z. Epigenetic repressionf miR-132 expression by the hepatitis B virus x proteinn hepatitis B virus-related hepatocellular carcinoma. Cell Signal. 2013, 25, 1037–1043. [Google Scholar] [CrossRef] [PubMed]
  91. Wang, Y.; Lu, Y.; Toh, S.T.; Sung, W.K.; Tan, P.; Chow, P.; Chung, A.Y.; Jooi, L.L.; Lee, C.G. Lethal-7sown-regulated by the hepatitis B virus x protein and targets signal transducer and activatorf transcription 3. J. Hepatol. 2010, 53, 57–66. [Google Scholar] [CrossRef] [PubMed]
  92. Johnson, S.M.; Grosshans, H.; Shingara, J.; Byrom, M.; Jarvis, R.; Cheng, A.; Labourier, E.; Reinert, K.L.; Brown, D.; Slack, F.J. RASs regulated by the let-7 microRNA family. Cell 2005, 120, 635–647. [Google Scholar] [CrossRef] [PubMed]
  93. Sampson, V.B.; Rong, N.H.; Han, J.; Yang, Q.; Aris, V.; Soteropoulos, P.; Petrelli, N.J.; Dunn, S.P.; Krueger, L.J. MicroRNA let-7aown-regulates MYC and reverts MYC-induced growthn Burkitt lymphoma cells. Cancer Res. 2007, 67, 9762–9770. [Google Scholar] [CrossRef] [PubMed]
  94. You, X.; Liu, F.; Zhang, T.; Lv, N.; Liu, Q.; Shan, C.; Du, Y.; Kong, G.; Wang, T.; Ye, L.; et al. Hepatitis B virus X protein upregulates Lin28A/Lin28B through Sp-1/c-Myc to enhance the proliferationf hepatoma cells. Oncogene 2014, 33, 449–460. [Google Scholar] [CrossRef] [PubMed]
  95. Piskounova, E.; Polytarchou, C.; Thornton, J.E.; LaPierre, R.J.; Pothoulakis, C.; Hagan, J.P.; Iliopoulos, D.; Gregory, R.I. Lin28A and Lin28Bnhibit let-7 microRNA biogenesis byistinct mechanisms. Cell 2011, 147, 1066–1079. [Google Scholar] [CrossRef] [PubMed]
  96. Mizuguchi, Y.; Mishima, T.; Yokomuro, S.; Arima, Y.; Kawahigashi, Y.; Shigehara, K.; Kanda, T.; Yoshida, H.; Uchida, E.; Tajiri, T.; et al. Sequencing and bioinformatics-based analysesf the microRNA transcriptomen hepatitis B-related hepatocellular carcinoma. PLoS ONE 2011, 6, e15304. [Google Scholar] [CrossRef] [PubMed]
  97. Wang, G.; Dong, F.; Xu, Z.; Sharma, S.; Hu, X.; Chen, D.; Zhang, L.; Zhang, J.; Dong, Q. MicroRNA profilen HBV-inducednfection and hepatocellular carcinoma. BMC Cancer 2017, 17, 805. [Google Scholar] [CrossRef] [PubMed]
  98. Wang, Y.; Jiang, L.; Ji, X.; Yang, B.; Zhang, Y.; Fu, X.D. Hepatitis B viral RNAirectly mediatesown-regulationf the tumor suppressor microRNA miR-15a/miR-16-1n hepatocytes. J. Biol. Chem. 2013, 288, 18484–18493. [Google Scholar] [CrossRef] [PubMed]
  99. Jung, Y.J.; Kim, J.W.; Park, S.J.; Min, B.Y.; Jang, E.S.; Kim, N.Y.; Jeong, S.H.; Shin, C.M.; Lee, S.H.; Park, Y.S.; et al. c-Myc-mediatedverexpressionf miR-17-92 suppresses replicationf hepatitis B virusn human hepatoma cells. J. Med. Virol. 2013, 85, 969–978. [Google Scholar] [CrossRef] [PubMed]
  100. Chen, Y.; Shen, A.; Rider, P.J.; Yu, Y.; Wu, K.; Mu, Y.; Hao, Q.; Liu, Y.; Gong, H.; Zhu, Y.; et al. A liver-specific microRNA binds to a highly conserved RNA sequencef hepatitis B virus and negatively regulates viral gene expression and replication. FASEB J. 2011, 25, 4511–4521. [Google Scholar] [CrossRef] [PubMed]
  101. Stubenrauch, F.; Hummel, M.; Iftner, T.; Laimins, L.A. The E8E2C protein, a negative regulatorf viral transcription and replication, is required for extrachromosomal maintenancef human papillomavirus type 31n keratinocytes. J. Virol. 2000, 74, 1178–1186. [Google Scholar] [CrossRef] [PubMed]
  102. Wang, X.; Meyers, C.; Wang, H.K.; Chow, L.T.; Zheng, Z.M. Constructionf a full transcription mapf human papillomavirus type 18uring productive viralnfection. J. Virol. 2011, 85, 8080–8092. [Google Scholar] [CrossRef] [PubMed]
  103. Lace, M.J.; Anson, J.R.; Thomas, G.S.; Turek, L.P.; Haugen, T.H. The E8–E2 gene productf human papillomavirus type 16 represses early transcription and replication butsispensable for viral plasmid persistencen keratinocytes. J. Virol. 2008, 82, 10841–10853. [Google Scholar] [CrossRef] [PubMed]
  104. Petti, L.; Nilson, L.A.; DiMaio, D. Activationf the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein. EMBO J. 1991, 10, 845–855. [Google Scholar] [PubMed]
  105. Bravo, I.G.; Alonso, A. Mucosal human papillomaviruses encode fourifferent E5 proteins whose chemistry and phylogeny correlate with malignantr benign growth. J. Virol. 2004, 78, 13613–13626. [Google Scholar] [CrossRef] [PubMed]
  106. Schiffman, M.; Herrero, R.; Desalle, R.; Hildesheim, A.; Wacholder, S.; Rodriguez, A.C.; Bratti, M.C.; Sherman, M.E.; Morales, J.; Guillen, D.; et al. The carcinogenicityf human papillomavirus types reflects viral evolution. Virology 2005, 337, 76–84. [Google Scholar] [CrossRef] [PubMed]
  107. Scheffner, M.; Werness, B.A.; Huibregtse, J.M.; Levine, A.J.; Howley, P.M. The E6ncoprotein encoded by human papillomavirus types 16 and 18 promotes theegradationf p53. Cell 1990, 63, 1129–1136. [Google Scholar] [CrossRef]
  108. Mortensen, F.; Schneider, D.; Barbic, T.; Sladewska-Marquardt, A.; Kuhnle, S.; Marx, A.; Scheffner, M. Rolef ubiquitin and the HPV E6ncoproteinn E6AP-mediated ubiquitination. Proc. Natl. Acad. Sci. USA 2015, 112, 9872–9877. [Google Scholar] [CrossRef] [PubMed]
  109. Munger, K.; Howley, P.M. Human papillomavirusmmortalization and transformation functions. Virus Res. 2002, 89, 213–228. [Google Scholar] [CrossRef]
  110. Vinokurova, S.; Wentzensen, N.; Kraus, I.; Klaes, R.; Driesch, C.; Melsheimer, P.; Kisseljov, F.; Durst, M.; Schneider, A.; von Knebel Doeberitz, M. Type-dependentntegration frequencyf human papillomavirus genomesn cervical lesions. Cancer Res. 2008, 68, 307–313. [Google Scholar] [CrossRef] [PubMed]
  111. Wan, Y.; Vagenas, D.; Salazar, C.; Kenny, L.; Perry, C.; Calvopina, D.; Punyadeera, C. Salivary miRNA panel toetect HPV-positive and HPV-negative head and neck cancer patients. Oncotarget 2017, 8, 99990–100001. [Google Scholar] [CrossRef] [PubMed]
  112. Pereira, P.M.; Marques, J.P.; Soares, A.R.; Carreto, L.; Santos, M.A. MicroRNA expression variabilityn human cervical tissues. PLoS ONE 2010, 5, e11780. [Google Scholar] [CrossRef] [PubMed]
  113. Li, Y.; Wang, F.; Xu, J.; Ye, F.; Shen, Y.; Zhou, J.; Lu, W.; Wan, X.; Ma, D.; Xie, X. Progressive miRNA expression profilesn cervical carcinogenesis anddentificationf HPV-related target genes for miR-29. J. Pathol. 2011, 224, 484–495. [Google Scholar] [CrossRef] [PubMed]
  114. Wang, X.; Wang, H.K.; Li, Y.; Hafner, M.; Banerjee, N.S.; Tang, S.; Briskin, D.; Meyers, C.; Chow, L.T.; Xie, X.; et al. microRNAs are biomarkersfncogenic human papillomavirusnfections. Proc. Natl. Acad. Sci. USA 2014, 111, 4262–4267. [Google Scholar] [CrossRef] [PubMed]
  115. Gao, D.; Zhang, Y.; Zhu, M.; Liu, S.; Wang, X. miRNA Expression Profilesf HPV-Infected Patients with Cervical Cancern the Uyghur Populationn China. PLoS ONE 2016, 11, e0164701. [Google Scholar] [CrossRef] [PubMed]
  116. Wald, A.I.; Hoskins, E.E.; Wells, S.I.; Ferris, R.L.; Khan, S.A. Alterationf microRNA profilesn squamous cell carcinomaf the head and neck cell lines by human papillomavirus. Head Neck 2011, 33, 504–512. [Google Scholar] [CrossRef] [PubMed]
  117. Lajer, C.B.; Nielsen, F.C.; Friis-Hansen, L.; Norrild, B.; Borup, R.; Garnaes, E.; Rossing, M.; Specht, L.; Therkildsen, M.H.; Nauntofte, B.; et al. Different miRNA signaturesfral and pharyngeal squamous cell carcinomas: A prospective translational study. Br. J. Cancer 2011, 104, 830–840. [Google Scholar] [CrossRef] [PubMed]
  118. Lajer, C.B.; Garnaes, E.; Friis-Hansen, L.; Norrild, B.; Therkildsen, M.H.; Glud, M.; Rossing, M.; Lajer, H.; Svane, D.; Skotte, L.; et al. The rolef miRNAsn human papilloma virus (HPV)-associated cancers: Bridging between HPV-related head and neck cancer and cervical cancer. Br. J. Cancer 2012, 106, 1526–1534. [Google Scholar] [CrossRef] [PubMed]
  119. Hui, A.B.; Lin, A.; Xu, W.; Waldron, L.; Perez-Ordonez, B.; Weinreb, I.; Shi, W.; Bruce, J.; Huang, S.H.; O’Sullivan, B.; et al. Potentially prognostic miRNAsn HPV-associatedropharyngeal carcinoma. Clin. Cancer Res. 2013, 19, 2154–2162. [Google Scholar] [CrossRef] [PubMed]
  120. Miller, D.L.; Davis, J.W.; Taylor, K.H.; Johnson, J.; Shi, Z.; Williams, R.; Atasoy, U.; Lewis, J.S., Jr.; Stack, M.S. Identificationf a human papillomavirus-associatedncogenic miRNA paneln humanropharyngeal squamous cell carcinoma validated by bioinformatics analysisf the Cancer Genome Atlas. Am. J. Pathol. 2015, 185, 679–692. [Google Scholar] [CrossRef] [PubMed]
  121. Vojtechova, Z.; Sabol, I.; Salakova, M.; Smahelova, J.; Zavadil, J.; Turek, L.; Grega, M.; Klozar, J.; Prochazka, B.; Tachezy, R. Comparisonf the miRNA profilesn HPV-positive and HPV-negative tonsillar tumors and a model systemf human keratinocyte clones. BMC Cancer 2016, 16. [Google Scholar] [CrossRef] [PubMed]
  122. Marur, S.; D’Souza, G.; Westra, W.H.; Forastiere, A.A. HPV-associated head and neck cancer: A virus-related cancer epidemic. Lancet Oncol. 2010, 11, 781–789. [Google Scholar] [CrossRef]
  123. Nasman, A.; Attner, P.; Hammarstedt, L.; Du, J.; Eriksson, M.; Giraud, G.; Ahrlund-Richter, S.; Marklund, L.; Romanitan, M.; Lindquist, D.; et al. Incidencef human papillomavirus (HPV) positive tonsillar carcinoman Stockholm, Sweden: An epidemicf viral-induced carcinoma? Int. J. Cancer 2009, 125, 362–366. [Google Scholar] [CrossRef] [PubMed]
  124. Harden, M.E.; Prasad, N.; Griffiths, A.; Munger, K. Modulationf microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins. mBio 2017, 8. [Google Scholar] [CrossRef] [PubMed]
  125. Emmrich, S.; Putzer, B.M. Checks and balances: E2F-microRNA crosstalkn cancer control. Cell Cycle 2010, 9, 2555–2567. [Google Scholar] [CrossRef] [PubMed]
  126. Myklebust, M.P.; Bruland, O.; Fluge, O.; Skarstein, A.; Balteskard, L.; Dahl, O. MicroRNA-15bsnduced with E2F-controlled genesn HPV-related cancer. Br. J. Cancer 2011, 105, 1719–1725. [Google Scholar] [CrossRef] [PubMed]
  127. Wang, X.; Wang, H.K.; McCoy, J.P.; Banerjee, N.S.; Rader, J.S.; Broker, T.R.; Meyers, C.; Chow, L.T.; Zheng, Z.M. Oncogenic HPVnfectionnterrupts the expressionf tumor-suppressive miR-34a through viralncoprotein E6. RNA 2009, 15, 637–647. [Google Scholar] [CrossRef] [PubMed]
  128. Au Yeung, C.L.; Tsang, T.Y.; Yau, P.L.; Kwok, T.T. Human papillomavirus type 16 E6nduces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway. Oncogene 2011, 30, 2401–2410. [Google Scholar] [CrossRef] [PubMed]
  129. Zhu, L.; Chen, H.; Zhou, D.; Li, D.; Bai, R.; Zheng, S.; Ge, W. MicroRNA-9 up-regulationsnvolvedn colorectal cancer metastasis via promoting cell motility. Med. Oncol. 2012, 29, 1037–1043. [Google Scholar] [CrossRef] [PubMed]
  130. Liu, W.; Gao, G.; Hu, X.; Wang, Y.; Schwarz, J.K.; Chen, J.J.; Grigsby, P.W.; Wang, X. Activationf miR-9 by human papillomavirusn cervical cancer. Oncotarget 2014, 5, 11620–11630. [Google Scholar] [PubMed]
  131. Yamamoto, N.; Kinoshita, T.; Nohata, N.; Itesako, T.; Yoshino, H.; Enokida, H.; Nakagawa, M.; Shozu, M.; Seki, N. Tumor suppressive microRNA-218nhibits cancer cell migration andnvasion by targeting focal adhesion pathwaysn cervical squamous cell carcinoma. Int. J. Oncol. 2013, 42, 1523–1532. [Google Scholar] [CrossRef] [PubMed]
  132. Kinoshita, T.; Hanazawa, T.; Nohata, N.; Kikkawa, N.; Enokida, H.; Yoshino, H.; Yamasaki, T.; Hidaka, H.; Nakagawa, M.; Okamoto, Y.; et al. Tumor suppressive microRNA-218nhibits cancer cell migration andnvasion through targeting laminin-332n head and neck squamous cell carcinoma. Oncotarget 2012, 3, 1386–1400. [Google Scholar] [CrossRef] [PubMed]
  133. Jung, H.M.; Phillips, B.L.; Chan, E.K. miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3zeta. Mol. Cancer 2014, 13. [Google Scholar] [CrossRef] [PubMed]
  134. Feng, H.; Shuda, M.; Chang, Y.; Moore, P.S. Clonalntegrationf a polyomavirusn human Merkel cell carcinoma. Science 2008, 319, 1096–1100. [Google Scholar] [CrossRef] [PubMed]
  135. Alvarez-Arguelles, M.E.; Melon, S.; Rojo, S.; Fernandez-Blazquez, A.; Boga, J.A.; Palacio, A.; Vivanco, B.; de Oña, M. Detection and quantificationf Merkel cell polyomavirus. Analysisf Merkel cell carcinoma cases from 1977 to 2015. J. Med. Virol. 2017, 89, 2224–2229. [Google Scholar] [CrossRef] [PubMed]
  136. Rodig, S.J.; Cheng, J.; Wardzala, J.; DoRosario, A.; Scanlon, J.J.; Laga, A.C.; Martinez-Fernandez, A.; Barletta, J.A.; Bellizzi, A.M.; Sadasivam, S.; et al. Improvedetection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J. Clin. Investig. 2012, 122, 4645–4653. [Google Scholar] [CrossRef] [PubMed]
  137. Moens, U.; Van Ghelue, M.; Johannessen, M. Oncogenic potentialsf the human polyomavirus regulatory proteins. Cell Mol. Life Sci. 2007, 64, 1656–1678. [Google Scholar] [CrossRef] [PubMed]
  138. Yin, W.Y.; Lee, M.C.; Lai, N.S.; Lu, M.C. BK virus as a potentialncovirus for bladder cancern a renal transplant patient. J. Formos. Med. Assoc. 2015, 114, 373–374. [Google Scholar] [CrossRef] [PubMed]
  139. Polz, D.; Morshed, K.; Stec, A.; Podsiadlo, L.; Polz-Dacewicz, M. Do polyomavirus hominis strains BK and JC play a rolenral squamous cell carcinoma? Ann. Agric. Environ. Med. 2015, 22, 106–109. [Google Scholar] [CrossRef] [PubMed]
  140. Lin, P.Y.; Fung, C.Y.; Chang, F.P.; Huang, W.S.; Chen, W.C.; Wang, J.Y.; Chang, D. Prevalence and genotypedentificationf human JC virusn colon cancern Taiwan. J. Med. Virol. 2008, 80, 1828–1834. [Google Scholar] [CrossRef] [PubMed]
  141. Houben, R.; Shuda, M.; Weinkam, R.; Schrama, D.; Feng, H.; Chang, Y.; Moore, P.S.; Becker, J.C. Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expressionf viral T antigens. J. Virol. 2010, 84, 7064–7072. [Google Scholar] [CrossRef] [PubMed]
  142. Sullivan, C.S.; Grundhoff, A.T.; Tevethia, S.; Pipas, J.M.; Ganem, D. SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells. Nature 2005, 435, 682–686. [Google Scholar] [CrossRef] [PubMed]
  143. Seo, G.J.; Fink, L.H.; O’Hara, B.; Atwood, W.J.; Sullivan, C.S. Evolutionarily conserved functionf a viral microRNA. J. Virol. 2008, 82, 9823–9828. [Google Scholar] [CrossRef] [PubMed]
  144. Bauman, Y.; Nachmani, D.; Vitenshtein, A.; Tsukerman, P.; Drayman, N.; Stern-Ginossar, N.; Lankry, D.; Gruda, R.; Mandelboim, O. Andentical miRNAf the human JC and BK polyoma viruses targets the stress-induced ligand ULBP3 to escapemmune elimination. Cell Host Microbe 2011, 9, 93–102. [Google Scholar] [CrossRef] [PubMed]
  145. Seo, G.J.; Chen, C.J.; Sullivan, C.S. Merkel cell polyomavirus encodes a microRNA with the ability to autoregulate viral gene expression. Virology 2009, 383, 183–187. [Google Scholar] [CrossRef] [PubMed]
  146. Lee, S.; Paulson, K.G.; Murchison, E.P.; Afanasiev, O.K.; Alkan, C.; Leonard, J.H.; Byrd, D.R.; Hannon, G.J.; Nghiem, P. Identification and validationf a novel mature microRNA encoded by the Merkel cell polyomavirusn human Merkel cell carcinomas. J. Clin. Virol. 2011, 52, 272–275. [Google Scholar] [CrossRef] [PubMed]
  147. Renwick, N.; Cekan, P.; Masry, P.A.; McGeary, S.E.; Miller, J.B.; Hafner, M.; Li, Z.; Mihailovic, A.; Morozov, P.; Brown, M.; et al. Multicolor microRNA FISH effectivelyifferentiates tumor types. J. Clin. Investig. 2013, 123, 2694–2702. [Google Scholar] [CrossRef] [PubMed]
  148. Martel-Jantin, C.; Filippone, C.; Cassar, O.; Peter, M.; Tomasic, G.; Vielh, P.; Briere, J.; Petrella, T.; Aubriot-Lorton, M.H.; Mortier, L.; et al. Genetic variability andntegrationf Merkel cell polyomavirusn Merkel cell carcinoma. Virology 2012, 426, 134–142. [Google Scholar] [CrossRef] [PubMed]
  149. Chen, C.J.; Cox, J.E.; Azarm, K.D.; Wylie, K.N.; Woolard, K.D.; Pesavento, P.A.; Sullivan, C.S. Identificationf a polyomavirus microRNA highly expressedn tumors. Virology 2015, 476, 43–53. [Google Scholar] [CrossRef] [PubMed]
  150. Brostoff, T.; Dela Cruz, F.N., Jr.; Church, M.E.; Woolard, K.D.; Pesavento, P.A. The raccoon polyomavirus genome and tumor antigen transcription are stable and abundantn neuroglial tumors. J. Virol. 2014, 88, 12816–12824. [Google Scholar] [CrossRef] [PubMed]
  151. Xie, H.; Lee, L.; Caramuta, S.; Hoog, A.; Browaldh, N.; Bjornhagen, V.; Larsson, C.; Lui, W.O. MicroRNA expression patterns related to merkel cell polyomavirusnfectionn human merkel cell carcinoma. J. Investig. Dermatol. 2014, 134, 507–517. [Google Scholar] [CrossRef] [PubMed]
  152. Chen, S.L.; Morgan, T.R. The natural history of hepatitis C virus (HCV) infection. Int. J. Med. Sci. 2006, 3, 47–52. [Google Scholar] [CrossRef] [PubMed]
  153. Fiorino, S.; Bacchi-Reggiani, L.; de Biase, D.; Fornelli, A.; Masetti, M.; Tura, A.; Grizzi, F.; Zanello, M.; Mastrangelo, L.; Lombardi, R.; et al. Possible association between hepatitis C virus and malignanciesifferent from hepatocellular carcinoma: A systematic review. World J. Gastroenterol. 2015, 21, 12896–12953. [Google Scholar] [CrossRef] [PubMed]
  154. Vescovo, T.; Refolo, G.; Vitagliano, G.; Fimia, G.M.; Piacentini, M. Molecular mechanismsf hepatitis C virus-induced hepatocellular carcinoma. Clin. Microbiol. Infect. 2016, 22, 853–861. [Google Scholar] [CrossRef] [PubMed]
  155. Pfeffer, S.; Sewer, A.; Lagos-Quintana, M.; Sheridan, R.; Sander, C.; Grasser, F.A.; van Dyk, L.F.; Ho, C.K.; Shuman, S.; Chien, M.; et al. Identificationf microRNAsf the herpesvirus family. Nat. Methods 2005, 2, 269–276. [Google Scholar] [CrossRef] [PubMed]
  156. Jopling, C.L.; Yi, M.; Lancaster, A.M.; Lemon, S.M.; Sarnow, P. Modulationf hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 2005, 309, 1577–1581. [Google Scholar] [CrossRef] [PubMed]
  157. Roberts, A.P.; Lewis, A.P.; Jopling, C.L. miR-122 activates hepatitis C virus translation by a specialized mechanism requiring particular RNA components. Nucleic Acids Res. 2011, 39, 7716–7729. [Google Scholar] [CrossRef] [PubMed]
  158. Machlin, E.S.; Sarnow, P.; Sagan, S.M. Masking the 5′ terminal nucleotidesf the hepatitis C virus genome by an unconventional microRNA-target RNA complex. Proc. Natl. Acad. Sci. USA 2011, 108, 3193–3198. [Google Scholar] [CrossRef] [PubMed]
  159. Lanford, R.E.; Hildebrandt-Eriksen, E.S.; Petri, A.; Persson, R.; Lindow, M.; Munk, M.E.; Kauppinen, S.; Orum, H. Therapeutic silencingf microRNA-122n primates with chronic hepatitis C virusnfection. Science 2010, 327, 198–201. [Google Scholar] [CrossRef] [PubMed]
  160. Janssen, H.L.; Reesink, H.W.; Lawitz, E.J.; Zeuzem, S.; Rodriguez-Torres, M.; Patel, K.; vaner Meer, A.J.; Patick, A.K.; Chen, A.; Zhou, Y.; et al. Treatmentf HCVnfection by targeting microRNA. N. Engl. J. Med. 2013, 368, 1685–1694. [Google Scholar] [CrossRef] [PubMed]
  161. Murakami, Y.; Aly, H.H.; Tajima, A.; Inoue, I.; Shimotohno, K. Regulationf the hepatitis C virus genome replication by miR-199a. J. Hepatol. 2009, 50, 453–460. [Google Scholar] [CrossRef] [PubMed]
  162. Hou, J.; Lin, L.; Zhou, W.; Wang, Z.; Ding, G.; Dong, Q.; Qin, L.; Wu, X.; Zheng, Y.; Yang, Y.; et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 2011, 19, 232–243. [Google Scholar] [CrossRef] [PubMed]
  163. Cheng, J.C.; Yeh, Y.J.; Tseng, C.P.; Hsu, S.D.; Chang, Y.L.; Sakamoto, N.; Huang, H.D. Let-7bs a novel regulatorf hepatitis C virus replication. Cell Mol. Life Sci. 2012, 69, 2621–2633. [Google Scholar] [CrossRef] [PubMed]
  164. Mukherjee, A.; Shrivastava, S.; Bhanja Chowdhury, J.; Ray, R.; Ray, R.B. Transcriptional suppressionf miR-181c by hepatitis C virus enhances homeobox A1 expression. J. Virol. 2014, 88, 7929–7940. [Google Scholar] [CrossRef] [PubMed]
  165. Mukherjee, A.; Di Bisceglie, A.M.; Ray, R.B. Hepatitis C virus-mediated enhancementf microRNA miR-373mpairs the JAK/STAT signaling pathway. J. Virol. 2015, 89, 3356–3365. [Google Scholar] [CrossRef] [PubMed]
  166. Shirasaki, T.; Honda, M.; Shimakami, T.; Horii, R.; Yamashita, T.; Sakai, Y.; Sakai, A.; Okada, H.; Watanabe, R.; Murakami, S.; et al. MicroRNA-27a regulates lipid metabolism andnhibits hepatitis C virus replicationn human hepatoma cells. J. Virol. 2013, 87, 5270–5286. [Google Scholar] [CrossRef] [PubMed]
  167. Zhang, Y.; Wei, W.; Cheng, N.; Wang, K.; Li, B.; Jiang, X.; Sun, S. Hepatitis C virus-induced up-regulationf microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology 2012, 56, 1631–1640. [Google Scholar] [CrossRef] [PubMed]
  168. Huang, S.; Xie, Y.; Yang, P.; Chen, P.; Zhang, L. HCV core protein-inducedown-regulationf microRNA-152 promoted aberrant proliferation by regulating Wnt1n HepG2 cells. PLoS ONE 2014, 9, e81730. [Google Scholar] [CrossRef]
  169. Ishida, H.; Tatsumi, T.; Hosui, A.; Nawa, T.; Kodama, T.; Shimizu, S.; Hikita, H.; Hiramatsu, N.; Kanto, T.; Hayashi, N.; et al. Alterationsn microRNA expression profilen HCV-infected hepatoma cells:nvolvementf miR-491n regulationf HCV replication via the PI3 kinase/Akt pathway. Biochem. Biophys. Res. Commun. 2011, 412, 92–97. [Google Scholar] [CrossRef] [PubMed]
  170. Banaudha, K.; Kaliszewski, M.; Korolnek, T.; Florea, L.; Yeung, M.L.; Jeang, K.T.; Kumar, A. MicroRNA silencingf tumor suppressor DLC-1 promotes efficient hepatitis C virus replicationn primary human hepatocytes. Hepatology 2011, 53, 53–61. [Google Scholar] [CrossRef] [PubMed]
  171. Varnholt, H.; Drebber, U.; Schulze, F.; Wedemeyer, I.; Schirmacher, P.; Dienes, H.P.; Odenthal, M. MicroRNA gene expression profilef hepatitis C virus-associated hepatocellular carcinoma. Hepatology 2008, 47, 1223–1232. [Google Scholar] [CrossRef] [PubMed]
  172. Ura, S.; Honda, M.; Yamashita, T.; Ueda, T.; Takatori, H.; Nishino, R.; Sunakozaka, H.; Sakai, Y.; Horimoto, K.; Kaneko, S. Differential microRNA expression between hepatitis B and hepatitis C leadingisease progression to hepatocellular carcinoma. Hepatology 2009, 49, 1098–1112. [Google Scholar] [CrossRef] [PubMed]
  173. Bandiera, S.; Pernot, S.; El Saghire, H.; Durand, S.C.; Thumann, C.; Crouchet, E.; Ye, T.; Fofana, I.; Oudot, M.A.; Barths, J.; et al. Hepatitis C Virus-Induced Upregulationf MicroRNA miR-146a-5pn Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis. J. Virol. 2016, 90, 6387–6400. [Google Scholar] [CrossRef] [PubMed]
  174. Pineau, P.; Volinia, S.; McJunkin, K.; Marchio, A.; Battiston, C.; Terris, B.; Mazzaferro, V.; Lowe, S.W.; Croce, C.M.; Dejean, A. miR-221verexpression contributes to liver tumorigenesis. Proc. Natl. Acad. Sci. USA 2010, 107, 264–269. [Google Scholar] [CrossRef] [PubMed]
  175. Kannian, P.; Green, P.L. Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis. Viruses 2010, 2, 2037–2077. [Google Scholar] [CrossRef] [PubMed]
  176. Huang, J.; Wang, F.; Argyris, E.; Chen, K.; Liang, Z.; Tian, H.; Huang, W.; Squires, K.; Verlinghieri, G.; Zhang, H. Cellular microRNAs contribute to HIV-1 latencyn resting primary CD4+ T lymphocytes. Nat. Med. 2007, 13, 1241–1247. [Google Scholar] [CrossRef] [PubMed]
  177. Hakim, S.T.; Alsayari, M.; McLean, D.C.; Saleem, S.; Addanki, K.C.; Aggarwal, M.; Mahalingam, K.; Bagasra, O. A large numberf the human microRNAs target lentiviruses, retroviruses, and endogenous retroviruses. Biochem. Biophys. Res. Commun. 2008, 369, 357–362. [Google Scholar] [CrossRef] [PubMed]
  178. Ruggero, K.; Corradin, A.; Zanovello, P.; Amadori, A.; Bronte, V.; Ciminale, V.; D’Agostino, D.M. Rolef microRNAsn HTLV-1nfection and transformation. Mol. Aspects Med. 2010, 31, 367–382. [Google Scholar] [CrossRef] [PubMed]
  179. Bai, X.T.; Nicot, C. miR-28-3ps a cellular restriction factor thatnhibits human T cell leukemia virus, type 1 (HTLV-1) replication and virusnfection. J. Biol. Chem. 2015, 290, 5381–5390. [Google Scholar] [CrossRef] [PubMed]
  180. Piedade, D.; Azevedo-Pereira, J.M. MicroRNAs, HIV and HCV: A complex relation towards pathology. Rev. Med. Virol. 2016, 26, 197–215. [Google Scholar] [CrossRef] [PubMed]
  181. Triboulet, R.; Mari, B.; Lin, Y.L.; Chable-Bessia, C.; Bennasser, Y.; Lebrigand, K.; Cardinaud, B.; Maurin, T.; Barbry, P.; Baillat, V.; et al. Suppressionf microRNA-silencing pathway by HIV-1uring virus replication. Science 2007, 315, 1579–1582. [Google Scholar] [CrossRef] [PubMed]
  182. Chiang, K.; Sung, T.L.; Rice, A.P. Regulationf cyclin T1 and HIV-1 Replication by microRNAsn resting CD4+ T lymphocytes. J. Virol. 2012, 86, 3244–3252. [Google Scholar] [CrossRef] [PubMed]
  183. Sung, T.L.; Rice, A.P. miR-198nhibits HIV-1 gene expression and replicationn monocytes andts mechanismf action appears tonvolve repressionf cyclin T1. PLoS Pathog. 2009, 5, e1000263. [Google Scholar] [CrossRef] [PubMed]
  184. Zhang, H.S.; Wu, T.C.; Sang, W.W.; Ruan, Z. MiR-217snvolvedn Tat-induced HIV-1 long terminal repeat (LTR) transactivation byown-regulationf SIRT1. Biochim. Biophys. Acta 2012, 1823, 1017–1023. [Google Scholar] [CrossRef] [PubMed]
  185. Van Duyne, R.; Guendel, I.; Klase, Z.; Narayanan, A.; Coley, W.; Jaworski, E.; Roman, J.; Popratiloff, A.; Mahieux, R.; Kehn-Hall, K.; et al. Localization and sub-cellular shuttlingf HTLV-1 tax with the miRNA machinery. PLoS ONE 2012, 7, e40662. [Google Scholar] [CrossRef] [PubMed]
  186. Pichler, K.; Schneider, G.; Grassmann, R. MicroRNA miR-146a and furtherncogenesis-related cellular microRNAs areysregulatedn HTLV-1-transformed T lymphocytes. Retrovirology 2008, 5, 100. [Google Scholar] [CrossRef] [PubMed]
  187. Yeung, M.L.; Yasunaga, J.; Bennasser, Y.; Dusetti, N.; Harris, D.; Ahmad, N.; Matsuoka, M.; Jeang, K.T. Roles for microRNAs, miR-93 and miR-130b, and tumor protein 53-induced nuclear protein 1 tumor suppressorn cell growthysregulation by human T-cell lymphotrophic virus 1. Cancer Res. 2008, 68, 8976–8985. [Google Scholar] [CrossRef] [PubMed]
  188. Bellon, M.; Lepelletier, Y.; Hermine, O.; Nicot, C. Deregulationf microRNAnvolvedn hematopoiesis and themmune responsen HTLV-I adult T-cell leukemia. Blood 2009, 113, 4914–4917. [Google Scholar] [CrossRef] [PubMed]
  189. Yamagishi, M.; Nakano, K.; Miyake, A.; Yamochi, T.; Kagami, Y.; Tsutsumi, A.; Matsuda, Y.; Sato-Otsubo, A.; Muto, S.; Utsunomiya, A.; et al. Polycomb-mediated lossf miR-31 activates NIK-dependent NF-kappaB pathwayn adult T cell leukemia andther cancers. Cancer Cell 2012, 21, 121–135. [Google Scholar] [CrossRef] [PubMed]
  190. Vernin, C.; Thenoz, M.; Pinatel, C.; Gessain, A.; Gout, O.; Delfau-Larue, M.H.; Nazaret, N.; Legras-Lachuer, C.; Wattel, E.; Mortreux, F. HTLV-1 bZIP factor HBZ promotes cell proliferation and geneticnstability by activating OncomiRs. Cancer Res. 2014, 74, 6082–6093. [Google Scholar] [CrossRef] [PubMed]
  191. Jin, W.B.; Wu, F.L.; Kong, D.; Guo, A.G. HBV-encoded microRNA candidate andts target. Comput. Biol. Chem. 2007, 31, 124–126. [Google Scholar] [CrossRef] [PubMed]
  192. Yang, X.; Li, H.; Sun, H.; Fan, H.; Hu, Y.; Liu, M.; Li, X.; Tang, H. Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication. J. Virol. 2017, 91. [Google Scholar] [CrossRef] [PubMed]
  193. Wang, Y.Q.; Ren, Y.F.; Song, Y.J.; Xue, Y.F.; Zhang, X.J.; Cao, S.T.; Deng, Z.J.; Wu, J.; Chen, L.; Li, G.; et al. MicroRNA-581 promotes hepatitis B virus surface antigen expression by targeting Dicer and EDEM1. Carcinogenesis 2014, 35, 2127–2133. [Google Scholar] [CrossRef] [PubMed]
  194. Wang, F.; Sun, Y.; Ruan, J.; Chen, R.; Chen, X.; Chen, C.; Kreuze, J.F.; Fei, Z.; Zhu, X.; Gao, S. Using small RNAeep sequencingata toetect human viruses. BioMed. Res. Int. 2016, 2016, 2596782. [Google Scholar] [CrossRef] [PubMed]
  195. Selitsky, S.R.; Dinh, T.A.; Toth, C.L.; Kurtz, L.; Honda, M.; Struck, B.R.; Kaneko, S.; Vickers, K.C.; Lemon, S.M.; Sethupathy, P. Transcriptomic analysisf chronic hepatitis B and C and liver cancer reveals microRNA-mediated controlf cholesterol synthesis programs. mBio 2015, 6, e01500-15. [Google Scholar] [CrossRef] [PubMed]
  196. Selitsky, S.R.; Baran-Gale, J.; Honda, M.; Yamane, D.; Masaki, T.; Fannin, E.E.; Guerra, B.; Shirasaki, T.; Shimakami, T.; Kaneko, S.; et al. Small tRNA-derived RNAs arencreased and more abundant than microRNAsn chronic hepatitis B and C. Sci. Rep. 2015, 5, 7675. [Google Scholar] [CrossRef] [PubMed]
  197. Qian, K.; Pietila, T.; Ronty, M.; Michon, F.; Frilander, M.J.; Ritari, J.; Tarkkanen, J.; Paulin, L.; Auvinen, P.; Auvinen, E. Identification and validationf human papillomavirus encoded microRNAs. PLoS ONE 2013, 8, e70202. [Google Scholar] [CrossRef] [PubMed]
  198. Virtanen, E.; Pietila, T.; Nieminen, P.; Qian, K.; Auvinen, E. Low expression levelsf putative HPV encoded microRNAsn cervical samples. Springerplus 2016, 5. [Google Scholar] [CrossRef] [PubMed]
  199. Weng, S.L.; Huang, K.Y.; Weng, J.T.; Hung, F.Y.; Chang, T.H.; Lee, T.Y. Genome-wideiscoveryf viral microRNAs basedn phylogenetic analysis and structural evolutionf various human papillomavirus subtypes. Brief Bioinform. 2017. [Google Scholar] [CrossRef]
  200. Klase, Z.; Kale, P.; Winograd, R.; Gupta, M.V.; Heydarian, M.; Berro, R.; McCaffrey, T.; Kashanchi, F. HIV-1 TAR elements processed by Dicer to yield a viral micro-RNAnvolvedn chromatin remodelingf the viral LTR. BMC Mol. Biol. 2007, 8, 63. [Google Scholar] [CrossRef] [PubMed]
  201. Ouellet, D.L.; Plante, I.; Landry, P.; Barat, C.; Janelle, M.E.; Flamand, L.; Tremblay, M.J.; Provost, P. Identificationf functional microRNAs released through asymmetrical processingf HIV-1 TAR element. Nucleic Acids Res. 2008, 36, 2353–2365. [Google Scholar] [CrossRef] [PubMed]
  202. Rouha, H.; Thurner, C.; Mandl, C.W. Functional microRNA generated from a cytoplasmic RNA virus. Nucleic Acids Res. 2010, 38, 8328–8337. [Google Scholar] [CrossRef] [PubMed]
  203. Harwig, A.; Jongejan, A.; van Kampen, A.H.C.; Berkhout, B.; Das, A.T. Tat-dependent productionf an HIV-1 TAR-encoded miRNA-like small RNA. Nucleic Acids Res. 2016, 44, 4340–4353. [Google Scholar] [CrossRef] [PubMed]
  204. Bernard, M.A.; Zhao, H.; Yue, S.C.; Anandaiah, A.; Koziel, H.; Tachado, S.D. Novel HIV-1 miRNAs stimulate TNFalpha releasen human macrophages via TLR8 signaling pathway. PLoS ONE 2014, 9, e106006. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Li, L.; Feng, H.; Da, Q.; Jiang, H.; Chen, L.; Xie, L.; Huang, Q.; Xiong, H.; Luo, F.; Kang, L.; et al. Expressionf HIV-encoded microRNA-TAR andtsnhibitory effectn viral replicationn human primary macrophages. Arch. Virol. 2016, 161, 1115–1123. [Google Scholar] [CrossRef] [PubMed]
  206. Klase, Z.; Winograd, R.; Davis, J.; Carpio, L.; Hildreth, R.; Heydarian, M.; Fu, S.; McCaffrey, T.; Meiri, E.; Ayash-Rashkovsky, M.; et al. HIV-1 TAR miRNA protects against apoptosis by altering cellular gene expression. Retrovirology 2009, 6. [Google Scholar] [CrossRef] [PubMed]
  207. Ouellet, D.L.; Vigneault-Edwards, J.; Letourneau, K.; Gobeil, L.A.; Plante, I.; Burnett, J.C.; Rossi, J.J.; Provost, P. Regulationf host gene expression by HIV-1 TAR microRNAs. Retrovirology 2013, 10. [Google Scholar] [CrossRef] [PubMed]
  208. Omoto, S.; Ito, M.; Tsutsumi, Y.; Ichikawa, Y.; Okuyama, H.; Brisibe, E.A.; Saksena, N.K.; Fujii, Y.R. HIV-1 nef suppression by virally encoded microRNA. Retrovirology 2004, 1, 44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  209. Swaminathan, G.; Navas-Martin, S.; Martin-Garcia, J. MicroRNAs and HIV-1nfection: Antiviral activities and beyond. J. Mol. Biol. 2014, 426, 1178–1197. [Google Scholar] [CrossRef] [PubMed]
  210. Kaul, D.; Ahlawat, A.; Gupta, S.D. HIV-1 genome-encoded hiv1-mir-H1mpairs cellular responses tonfection. Mol. Cell. Biochem. 2009, 323, 143–148. [Google Scholar] [CrossRef] [PubMed]
  211. Zhang, Y.; Fan, M.; Geng, G.; Liu, B.; Huang, Z.; Luo, H.; Zhou, J.; Guo, X.; Cai, W.; Zhang, H. A novel HIV-1-encoded microRNA enhancests viral replication by targeting the TATA box region. Retrovirology 2014, 11, 23. [Google Scholar] [CrossRef] [PubMed]
  212. Lin, J.; Cullen, B.R. Analysisf thenteractionf primate retroviruses with the human RNAnterference machinery. J. Virol. 2007, 81, 12218–12226. [Google Scholar] [CrossRef] [PubMed]
  213. Whisnant, A.W.; Bogerd, H.P.; Flores, O.; Ho, P.; Powers, J.G.; Sharova, N.; Stevenson, M.; Chen, C.; Cullen, B.R. In-depth analysisf thenteractionf HIV-1 with cellular microRNA biogenesis and effector mechanisms. mBio 2013, 4, e00193-13. [Google Scholar] [CrossRef] [PubMed]
  214. Schopman, N.C.; Willemsen, M.; Liu, Y.P.; Bradley, T.; van Kampen, A.; Baas, F.; Berkhout, B.; Haasnoot, J. Deep sequencingf virus-infected cells reveals HIV-encoded small RNAs. Nucleic Acids Res. 2012, 40, 414–427. [Google Scholar] [CrossRef] [PubMed]
  215. Vongrad, V.; Imig, J.; Mohammadi, P.; Kishore, S.; Jaskiewicz, L.; Hall, J.; Günthard, H.F.; Beerenwinkel, N.; Metzner, K.J. HIV-1 RNAs are not partf the Argonaute 2 associated RNAnterference pathwayn macrophages. PLoS ONE 2015, 10, e0132127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  216. Kincaid, R.P.; Burke, J.M.; Sullivan, C.S. RNA virus microRNA that mimics a B-cellncomiR. Proc. Natl. Acad. Sci. USA 2012, 109, 3077–3082. [Google Scholar] [CrossRef] [PubMed]
  217. Li, Z.; Rana, T.M. Therapeutic targetingf microRNAs: Current status and future challenges. Nat. Rev. Drug Discov. 2014, 13, 622–638. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Viral miRNAs of Epstein–Barr virus (EBV), human herpesvirus 8 (HHV8) and Merkel cell polyomavirus (MCPyV), and cell miRNAs whose expression is influenced by the viral infection. The deregulation of these miRNAs contributes to the transformation of the cell and to tumor development. Green = viral miRNAs that target viral mRNAs, red = viral miRNAs that target cellular mRNAs, and yellow = cellular miRNAs influenced by the viral infection.
Figure 1. Viral miRNAs of Epstein–Barr virus (EBV), human herpesvirus 8 (HHV8) and Merkel cell polyomavirus (MCPyV), and cell miRNAs whose expression is influenced by the viral infection. The deregulation of these miRNAs contributes to the transformation of the cell and to tumor development. Green = viral miRNAs that target viral mRNAs, red = viral miRNAs that target cellular mRNAs, and yellow = cellular miRNAs influenced by the viral infection.
Ijms 19 01217 g001
Table 1. Summary of authentic viral-encoded miRNAs mentioned in the review, and their viral and cellular targets.
Table 1. Summary of authentic viral-encoded miRNAs mentioned in the review, and their viral and cellular targets.
Virus FamilyVirus SpeciesMature miRNAs (According to miRBase, Updated 2014)MiRNAs Mentioned in This ReviewProposed FunctionTargetReference
HerpesviridaeEpstein–Barr virus (EBV)44miR-BART17-5pcell transformationLMP1[25]
miR-BART16cell transformation, anti-apoptotic roleLMP1, Casp3[25,31]
miR-BART1-5pLMP1, Casp3[25,31]
miR-BART5-5pPUMA[29]
miR-BART19-5pPUMA[29]
miR-BART22escape from host immune surveillanceLMP2A[26]
miR-BART2-5p regulation of latent–lytic switch, evasion of the host‘s immune systemBALF5, MICB[27,36]
miR-BART6-5pregulation of viral replicationEBNA2[28]
miR-BART7-3ppromotion of EMT and metastasis, regulation of radiation sensitivityPTEN, GFPT1[30,38]
miR-BART3proliferation and cell transformationDICE1[32]
miR-BHRF1-1immunomodulatory functionCXCL11[33]
miR-BHRF1-2CXCL11
miR-BHRF1-3CXCL11
Herpesvirus-8 (HHV-8)/Kaposi’s sarcoma herpesvirus (KSHV)25miR-K9-5pregulation of lytic inductionRTA[54,55]
miR-K7-5p
miR-K3regulation of viral latency and angiogenesisnuclear factor I/B, GRK2, THBS1[56,62,63]
miR-K12-11MYB, IKKε, THBS1[58,60,62]
miR-K12-4regulation of viral latency, anti-apoptotic roleRbl2, Casp3[61,67]
miR-K6-3pregulation of angiogenesisTHBS1, SH3BGR[62,63]
miR-K12-1anti-apoptotic role, regulation of angiogenesisp21, Casp3, THBS1[62,66,67]
PolyomaviridaeMerkel cell polyomavirus (MCPyV)1MCV-miR-M1regulation of viral lifecycleearly viral transcripts[145]

Share and Cite

MDPI and ACS Style

Vojtechova, Z.; Tachezy, R. The Role of miRNAs in Virus-Mediated Oncogenesis. Int. J. Mol. Sci. 2018, 19, 1217. https://doi.org/10.3390/ijms19041217

AMA Style

Vojtechova Z, Tachezy R. The Role of miRNAs in Virus-Mediated Oncogenesis. International Journal of Molecular Sciences. 2018; 19(4):1217. https://doi.org/10.3390/ijms19041217

Chicago/Turabian Style

Vojtechova, Zuzana, and Ruth Tachezy. 2018. "The Role of miRNAs in Virus-Mediated Oncogenesis" International Journal of Molecular Sciences 19, no. 4: 1217. https://doi.org/10.3390/ijms19041217

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop