Search Results (188)

Epstein–Barr virus (EBV) is a highly prevalent oncogenic virus that establishes persistent infection in most of the human population and is strongly associated with several lymphoid and epithelial malignancies, particularly nasopharyngeal carcinoma, gastric carcinoma, and lymphoepithelial carcinoma. This review summarizes current knowledge on the relationship between EBV infection and apoptosis regulation in epithelial cancers, with emphasis on how viral persistence may contribute to tumor cell survival and therapeutic resistance. The manuscript reviews evidence on EBV genome organization, latent and lytic infection programs, the epidemiology of EBV-associated epithelial tumors, and the main intrinsic and extrinsic apoptotic pathways. It then discusses how viral proteins, including latent membrane proteins, Epstein–Barr nuclear antigen 1 (EBNA1), BHRF1, and BARF1, as well as EBV-encoded microRNAs, modulate key apoptotic regulators such as p53, Bcl-2 family members, death receptor pathways, and caspases. Current evidence indicates that EBV can promote apoptosis resistance through coordinated effects on mitochondrial and death receptor-mediated cell death. Understanding these mechanisms may help clarify the contribution of EBV to epithelial oncogenesis and support therapeutic strategies aimed at restoring apoptotic sensitivity in EBV-associated tumors. Full article

Human T-Lymphotropic virus type 1 (HTLV-1) lifelong infects at least 5–10 million people worldwide, a minority of whom develop severe lethal diseases including adult T-cell Leukemia/lymphoma and HTLV-1-associated myelopathy or tropical spastic paraparesis. Currently, no vaccines or curative therapies to fight HTLV-1 infection or diseases are available. Recently we found that a tributyltin molecule, Bu₃SnOCOCF₃ (TBT), which is more potent than cisplatin in inducing cytotoxic effects towards a panel of cell lines including high-tumorigenic cells, also exerted potent cytotoxic effects even towards HTLV-1-infected cell lines, mimicking different states of virus-driven transformation. The type of cell death involved was elusive. In the present study, the effects of TBT on virological and cell death parameters were investigated in HTLV-1-infected immortalized lymphocytes generated by in vitro infection and rendered with or without progressive independence from interleukin-2 as a growth factor. Molecular studies demonstrated that TBT affected HTLV-1 viral gene expression, especially HBZ. TBT confirmed its high cytotoxic potential on the HTLV-1-infected cell lines assayed, especially towards the IL-2-independent HTLV-1-infected cells. Investigation of mechanisms involved in cell death induced by TBT in HTLV-1-infected cells confirmed that caspase 3 and 8 activation, as well as apoptotic response, were relevant. In addition, pyroptosis as well as other unspecifed forms of lytic death presumably contribute to cell death induced by TBT in HTLV-1-infected cells, while a concomitant activation of an autophagic response by this compound seems to mitigate it. Overall, these experimental results outline a particular profile of TBT-induced cell death in HTLV-1-infected cells that is useful for future studies aimed at verifying the real potential of tin-based compounds to contrast diseases caused by HTLV-1. Full article

Genetically modified hematopoietic stem cell therapy using gene-modified autologous hematopoietic stem cells has evolved over the last 30 years as an alternative approach to circumvent the limitations of donor availability, risks of excessive regimen related toxicity, prolonged immune suppression and graft-versus-host disease associated with allogeneic hematopoietic cell transplantation. Gene replacement therapy based on viral insertion of transgene into host genome was developed as one of the main methods for gene modification of autologous cells. Unfortunately, many cases of oncogenesis were directly caused by genetically modified hematopoietic stem cell therapy. The purpose of the present review is the description of cases of leukemogenesis in gene replacement therapy in hematopoietic stem cells, elucidation of the causes, and overview of the risk mitigation strategies. It aims to elucidate the main risk factors in gene replacement therapy in hematopoietic stem cells. The insertional mutagenesis leads to activation of proto-oncogenes, mostly LMO2 and MECOM-EVI1. γ-retroviral vectors are dangerous in this case, as they contain long terminal repeats with strong promotor activity and are prone to integration near transcription initiation sites. Therefore, safer self-inactivating lentiviral vectors were developed, with long terminal repeats modified to reduce their promoter activity and with safer integration pattern. Nevertheless, the risk of leukemogenesis remains because the promoter integrated into the transgene expression cassette may still influence nearby gene expression. Another risk factor is monosomy 7, either pre-existing or caused by MECOM-EVI1 activation, which may contribute directly to leukemogenesis. Thus, oncogenesis in HSPC gene replacement therapy does not have a single definitive cause; rather, multiple factors may contribute, and each may be sufficient under specific conditions. Full article

Human T-cell leukemia virus-1 (HTLV-1) is the etiological agent of a series of chronic inflammatory diseases such as HTLV-associated myelopathy/Tropical spastic paraparesis (HAM/TSP), uveitis, dermatitis, and pneumonitis, and, importantly, of a T-cell lymphoproliferative neoplasm designed adult T-cell leukemia/lymphoma (ATL). Two viral proteins, Tax-1 and HBZ, are crucially involved in HTLV-1 infectivity and in ATL by altering key pathways of cell homeostasis. A fundamental distinction between the expression of the two oncoproteins exists, witnessed by the fact that Tax-1 is expressed in early phases of HTLV-1 infectivity and ATL onset but may be lost in a substantial number of established ATL, whereas HBZ is always expressed in all phases of HTLV-1 infection and in all ATL. Additionally, while Tax-1 can be localized both in the cytoplasm and nucleus in all cases of disease, recent evidence indicate that HBZ is localized solely in the cytoplasm in cells of HTLV-1-infected individuals, asymptomatic carriers (AC) and patients suffering from HAM/TSP. Importantly, ATL instead marks a progressive dislocation of HBZ in the nucleus. Thus, both the expression and the subcellular localization of HBZ represent distinctive elements in the process of HTLV-1-associated pathology. Within this frame, recent studies point to a very important involvement of HBZ in disarranging the homeostasis of the cell not only at the transcriptional but most importantly at the post-transcriptional level as a result of the interaction with crucial factors regulating RNA splicing and stability. These recent aspects of the HBZ biology will be discussed for their implication in HTLV-1-mediated oncogenesis. Full article

Oncogenic viruses are responsible for between 12% and 20% of human cancers worldwide. They trigger tumorigenesis by integrating into host-cell genomes, altering cell cycle pathways, and evading immune detection. Oncoviral cancers exhibit low rates of mutation, implicating alternative splicing as an underappreciated alternative mechanism for oncogene and oncogenic pathway activation in oncoviral pathogenesis and progression. In order to create alternatively spliced viral proteins for replication and viral genome maintenance, oncoviruses take advantage of host-cell splicing machinery. Some of these proteins inhibit major host-cell tumor suppressors to promote the proliferation of DNA-damaged host-cells in order to facilitate persistent infection, whilst others interact with and de-regulate the expression and activity of host-cell splicing factors to alter host transcript splice site selection. The latter reprograms host-cell transcriptomes to express aberrant, sometimes oncogenic protein isoforms, which interact with oncoviral proteins to promote host-cell transformation and subsequent tumor progression to metastatic disease. In this article, we review oncovirus-induced alternative splicing as a fundamental, underappreciated, oncogenic and tumor-promoting mechanism. We present detailed descriptions of individual human oncoviruses. We compare how these oncoviruses hijack host-cell splicing mechanisms, how specific aberrant alternatively spliced host-cell protein isoforms, induced by oncoviruses, influence tumor pathogenesis and progression, organized with respect to the hallmarks of cancer, and provide a section on therapeutic perspectives. This approach not only crystallizes the complexity of how oncovirus-induced host-cell alternative splicing can influence cancer pathogenesis and progression but also reveals novel potential therapeutic opportunities. Full article

Viral carcinogenesis as a causative mechanism of breast cancer has been intensively researched during the last decades. The role of Epstein–Barr virus (EBV) and Bovine Leukemia virus (BLV) in breast oncogenesis has been investigated in a plethora of studies, but with conflicting results. The aim of this systematic review and meta-analysis was to compare the frequency of molecular detection of the EBV genome and BLV genome between women with breast cancer and women without malignant breast tumors. This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE, SCOPUS, Cochrane CENTRAL and ClinicalTrials.gov were searched up to 20 May 2024. Included studies were those comparing the frequency of molecular detection of the EBV and/or BLV genome in breast tissue specimens with polymerase chain reaction (PCR) methods between patients with breast cancer and women without breast malignancies. The primary outcomes of the study were the frequency of molecular detection of the EBV genome and BLV genome. Methodological quality of included studies was assessed using the Newcastle–Ottawa Scale. A total of 29 studies met the selection criteria and were included in this meta-analysis; 19 studies reported results for molecular detection of the EBV genome, 9 studies for detection of the BLV genome and 1 study for detection of genomic material of both viruses. The frequency of molecular detection of viral genomes was significantly higher in patients with breast cancer, compared to women with healthy breasts or benign breast diseases, regarding both EBV (OR: 3.041, 95% CI: 1.791 to 5.164, p < 0.0001) and BLV (OR: 3.459, 95% CI: 2.118 to 5.650, p < 0.0001). The frequency of molecular detection of EBV and BLV genomes is higher, in a statistically significant manner, in patients with breast cancer compared to women without breast malignancies. The presence of these viral factors in breast tissue could imply their potential contribution in breast carcinogenesis, but is not sufficient to establish it, and the molecular detection of their genomes could be potentially exploited in the future for preventive, diagnostic and therapeutic purposes. Further studies are required to thoroughly investigate and establish a causal relationship between EBV and BLV infection and breast carcinogenesis, as well as to support the use of viral genome molecular detection in clinical settings for the management of breast cancer patients. Full article

Background/Objectives: Merkel cell polyomavirus (MCPyV) is a ubiquitous virus strictly associated with Merkel cell carcinoma (MCC), a rare and aggressive skin cancer. MCPyV oncogenic properties are associated mainly with early protein expression, integration, and LT truncation. MCPyV can also interact with DNA Damage Response (DDR) mechanisms, contributing to oncogenesis and tumor progression. In this work, we investigated the correlation between MCPyV and MCC and evaluated the mRNA expression profiles of DDR genes in virus-positive and -negative tumors. Methods: A total of 19 formalin-fixed paraffin-embedded biopsies were acquired from patients diagnosed with MCC. After DNA and RNA extraction, the DNA was used for MCPyV detection via qPCR and for sequencing analysis of the early, late, and non-coding control viral regions and the extracted RNA was used for MCPyV transcripts, miRNA detection and for the evaluation of several DDR genes expression such as ATM, ATR, CHK1, CHK2, H2AX, Rad51, p53, and p21, in MCPyV-positive and -negative samples via reverse transcription, PCR, and qPCR. Results: MCPyV presence was detected in 11/19 samples, all characterized by viral integration, LT truncation, and early region expression only. Furthermore, higher mRNA levels of DDR genes were observed in MCPyV-positive tumors compared with the negative ones. Conclusions: Our findings support the role of MCPyV in MCC formation and suggest its involvement in the transcriptional regulation of DDR genes, which may influence tumor progression. Understanding the molecular interplay between MCPyV and the DDR may guide future research into plausible novel diagnostic and therapeutic strategies for virus-induced tumors. Full article

Background/Objectives: Kaposi’s sarcoma (KS) is an angioproliferative malignancy caused by Kaposi’s sarcoma-associated herpesvirus (KSHV), characterized by aberrant angiogenesis, chronic inflammation, and endothelial cell transformation. Given the multi-factorial nature of KS pathogenesis, strategies that simultaneously modulate multiple mo-lecular targets are considered more promising than single-target approaches. However, effective multi-target therapeutic agents for KS remain limited, prompting this study to employ an integrative in silico pipeline. Methods: An integrative in silico pipeline combining compound screening, target predic-tion, network pharmacology, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Ge-nomes (KEGG) enrichment, protein–protein interaction (PPI) analysis, molecular docking, and molecular dynamics (MD) simulations was employed. Streptomyces-derived metabolites were prioritized based on chemical diversity, annotation, and clinical prece-dent. Predicted targets were intersected with KS-associated genes, with hubs ranked by network topology. Docking and MD simulations evaluated binding affinity and stability. Results: Endostemonine I emerged as the top candidate, engaging nine of ten hub proteins, including EGFR, mTOR, PTGS2, SRC, PARP1, PPARγ, MAPK1, MAPK14, and ICAM1. Key nodes such as mTOR, PTGS2, PPARγ, and MAPK14 are central to KS-related an-gi-ogenesis, inflammation, and viral oncogenesis. GO and KEGG analyses revealed en-richment in kinase activity, cell adhesion, and PI3K–Akt/mTOR and MAPK signaling pathways. Docking indicated strong binding to mTOR, PTGS2, PARP1, PPARγ, and MAPK14, while MD simulations confirmed stable interactions for mTOR, PTGS2, PPARγ, and MAPK14. Conclusions: Collectively, these proteins represent high-confidence, druggable KS targets, with Endostemonine I as a promising multi-target scaffold. These findings highlight the therapeutic potential of Endostemonine I and warrant further validation through future in vitro and in vivo studies. Full article

Adenoviruses have been implicated in childhood cancers, primarily leukemia, yet prior neonatal investigations have rarely examined other pediatric tumor types. This study evaluated whether adenoviral early region (E1A) sequences can be detected in archival neonatal Guthrie cards from children who later developed diverse pediatric tumors and in corresponding paraffin-embedded tissues. DNA extraction was optimized for long-stored dried blood spots, and PCR conditions were refined for both Guthrie card and paraffin-derived DNA. Adenoviral E1A was analyzed using conventional and nested PCR, and sequencing of representative amplicons confirmed correspondence to human adenovirus species C. E1A PCR positivity was found in 43% of Guthrie cards from cases (n = 54) and 34% of controls (n = 32), and in 41% of tumor tissues (n = 75) compared with 5% of non-tumor paraffin controls (n = 20). Detection occurred across multiple tumor categories without a clear association with tumor type. Partial concordance was observed between paired neonatal and tumor samples, and cytomegalovirus markers were detected in a subset of E1A-positive specimens. These findings confirm the suitability of Guthrie cards for retrospective viral DNA detection and extend previous leukemia-focused neonatal studies to broader pediatric tumors. The data suggest a potential association between birth-stage adenoviral detection and childhood cancer, though a causal link remains unproven and requires further longitudinal investigation. Full article

Background: People living with HIV (PLWH) have a substantially increased risk of both AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs), which remain a major cause of morbidity despite effective antiretroviral therapy (ART); this review aims to integrate current epidemiological, molecular, and clinical evidence on HIV-associated oncogenesis. Methods: A structured literature search was conducted in PubMed (2000–2026) using predefined keywords, including “HIV”, “cancer”, “oncogenesis”, and “immune dysregulation”, with inclusion of original studies, systematic reviews, and meta-analyses meeting predefined quality criteria. Results: Available evidence indicates that HIV contributes to cancer development through both direct and indirect mechanisms: viral proteins such as Tat, Nef, and Vpr disrupt apoptosis, DNA repair, and cell cycle regulation, while chronic immune activation, persistent inflammation, and immunosuppression impair tumor immune surveillance and facilitate oncogenic viral co-infections, including Epstein–Barr virus, human papillomavirus, and human herpesvirus 8. Emerging pathways, such as epigenetic alterations, microRNA dysregulation, metabolic reprogramming, and the contribution of HIV reservoirs to pro-tumorigenic microenvironments, further modulate cancer risk. Conclusions: HIV may function as a cofactor that enhances the effects of oncogenic viruses by promoting viral persistence and immune dysregulation; while biologically plausible, direct evidence linking HIV to amplification of tumorigenesis in humans remains limited. Full article

Merkel Cell Polyomavirus is an oncogenic virus associated with Merkel Cell Carcinoma (MCC). However, considering viral detection in respiratory specimens and similarities between MCC and neuroendocrine lung cancer, its plausible role in the respiratory tract is disputed. MCPyV-mediated oncogenesis involves viral antigens interfering with host signaling as a DNA Damage Response (DDR). In the current study, respiratory models, including lung cancer cell lines (A549 and H1299), and non-malignant bronchial systems (HBEC-KT and a 2D ALI model) were used to investigate DDR genes’ expression following MCPyV infection. Once the capability to support viral replication and transcription was assessed using qPCR and RT-qPCR, respectively, the mRNA levels of DDR genes, including ATM, ATR, Chk1, Chk2, H2AX, Rad51, p53 and p21, were examined. Our findings showed MCPyV replication in all cellular systems, as proven by the detection of viral DNA and transcripts. Viral infection induced an overexpression of DDR genes, suggesting a role of the virus in manipulating DDR to favor its replication or contribute to tumor progression. These preliminary results provide in vitro models for studying the interplay between MCPyV and DDR within malignant and non-malignant contexts across the respiratory tract, laying the basis for future research exploring the clinical relevance of DDR activation in virus-driven malignancies. Full article

Human papillomavirus (HPV), especially high-risk HPV types, is a significant public health concern due to its association with various cancers and increased risk of acquiring other sexually transmitted infections (STIs). In most cases, host immunity rapidly responds to and clears HPV infections, but persistent or latent infections can increase susceptibility to cancer. A better understanding of how HPV interacts with and evades the immune response is vital to understanding disease progression and guiding the next generation of vaccines and immunotherapies. This review article provides a comprehensive overview of the immune mechanisms involved in HPV infection, highlighting the roles of T cells and other immune subsets. We discuss the immune evasion strategies employed by HPV and subsequent modulation of the immune microenvironment. Additionally, we explore the current therapeutic landscape and emerging immunotherapeutic approaches under investigation. By unveiling the intricacies of the immune response to HPV, we may inform improved strategies for the treatment of HPV-related diseases. Full article

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection induces heterogeneous immune responses that influence both acute disease severity and long-term immune remodeling. A key question in the context of infection and vaccination is whether SARS-CoV-2 exerts direct oncogenic effects or instead acts as a transient immunological stressor capable of reinforcing tumor-permissive pathways. Current evidence does not support classical viral oncogenesis. Rather, severe infection is characterized by early interferon (IFN) imbalance followed by NF-κB-dominant inflammatory amplification, promoting sustained IL-6/JAK–STAT3 and MAPK signaling, chronic cytokine production, metabolic reprogramming, and impaired antitumor immune surveillance. At the molecular level, viral structural proteins modulate host signaling networks. The spike (S1) protein engages TLR2/TLR4–MyD88 pathways, activating NF-κB and MAPK cascades, while the membrane (M) protein reinforces NF-κB–STAT3 circuits linked to epithelial–mesenchymal transition and inflammatory gene expression. These mechanisms intensify pre-existing oncogenic signaling without initiating malignant transformation. Tissue-specific responses are further shaped by IFN competence, renin–angiotensin system balance, and metabolic context. In parallel, immune evasion programs shared by chronic viral infection and cancer, including checkpoint upregulation, impaired antigen presentation, and suppressive myeloid expansion, may be transiently reinforced following severe infection. In contrast, SARS-CoV-2 vaccination induces spatially restricted, self-limited innate activation without sustained inflammatory signaling or persistent antigen exposure. By preventing severe disease and chronic immune dysregulation, vaccination interrupts pathways hypothesized to intersect with cancer biology, with no evidence of increased cancer incidence. Ongoing longitudinal studies are required to clarify the long-term oncologic implications of post-infectious immune remodeling. Full article

Persistent oncovirus infections account for 15–20% of the global cancer burden, driving multiple forms of human cancer. To maintain persistent infection and spread, oncoviruses drive alterations in host cell metabolism, immune signaling, and cell-to-cell communication throughout tumor microenvironments. Accumulating evidence has indicated that these alterations occur in conjunction with a range of organelle remodeling events that can differ between “dormant” viral latency and active lytic replication. Throughout each phase of infection, oncoviruses alter the morphology, composition, and function of organelles to promote cellular survival and proliferation, while periodically supporting viral replication. Here, we review oncovirus-driven organelle remodeling strategies across distinct infection states, including viral latency, reactivation from latency, and chronic active replication. We focus on the molecular mechanisms by which oncovirus-driven organelle remodeling promotes cellular transformation, impedes immune responses, and facilitates virion assembly and egress. We also draw parallels between remodeling strategies employed by oncogenic and oncomodulatory viruses, emphasizing broadly conserved mechanisms across cancer-associated infections. Lastly, we highlight how studies of oncovirus organelle remodeling are critical for discovering vulnerabilities in both oncogenic virus infection and viral oncogenesis, with therapeutic potential for multiple cancers. Full article

The hepatitis C virus (HCV) Core activates the ATM-Chk2 pathway, leading to phosphorylation of p53 at Ser-15, which inhibits mouse double minute 2 (MDM2)-mediated proteasomal degradation. This study reveals that HCV Core also promotes E6-associated protein (E6AP)-mediated degradation of p53 during HCV replication. In the presence of HCV Core, E6AP expression induced p53 ubiquitination, reduced its stability, and decreased p53 levels, whereas E6AP knockdown increased p53 levels. The E3 ubiquitin ligase activity of E6AP was critical for this process, as demonstrated using the E6AP C833A mutant and the E3 ligase inhibitor Heclin. Proteasomal inhibition with MG132 confirmed that HCV Core and E6AP act together to regulate p53 levels via the proteasome. Importantly, HCV Core-induced p53 phosphorylation was essential for E6AP-mediated degradation, as shown by the impairment of degradation in the presence of the ATM inhibitor KU-55933. E6AP also targeted p53 phosphorylated at Ser-15 by etoposide, as well as phosphomimetic mutants such as p53 S15D, but not non-phosphorylatable mutants such as p53 S15A. These findings suggest that HCV Core-induced p53 phosphorylation enhances E6AP-mediated degradation while preventing MDM2 from targeting p53, thereby maintaining p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes. Full article