Search Results (13)

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

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

Approximately 12% of all human cancers are caused by oncoviruses. Macrophage migration inhibitory factor (MIF) signaling activation has been found closely related to many cancer cell malignant behaviors and infectious disease progression. However, its role in virus-associated cancers or how oncoviruses may regulate MIF signaling activities remains largely unknown. In the current review, we summarize recent findings about the oncovirus activation of MIF signaling pathways, their functional roles in viral oncogenesis, and the development of MIF-targeted therapies. We also discuss future directions in this interesting field. Full article

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies. Full article

Epstein–Barr virus (EBV), a member of the gamma herpesvirus, is the first identified human oncovirus and is associated with various malignancies. Understanding the intricate interactions between EBV antigens and cellular pathways is crucial to unraveling the molecular mechanisms in EBV-mediated diseases. However, fully elucidating EBV–host interactions and the associated pathogenesis remains a significant challenge. In this study, we employed large language models (LLMs) to screen 36,105 EBV-relevant scientific publications and summarize the current literature landscape on various EBV-associated diseases like Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and so on. LLM-generated data indicate that the most-studied EBV-associated pathways are enriched in immune response, apoptosis, cell growth, and replication. The analyses of protein–protein interactions (PPIs) reveal three principal EBV-related protein clusters: TP53-centered apoptotic factors, EBV-associated transcription factors, and immune response elements. Utilizing our dataset and public databases, we demonstrated that BLLF3-targeted TLR2-associated factors are effective diagnostic markers for DLBCL. Next, we confirmed the co-expression of LMP1-targeted calcium pathway factors in BL. Finally, we demonstrated the correlation and co-expression of LMP1-induced PARP1, HIF1A, HK2, and key glycolysis-related factors, further suggesting that LMP1 actively regulates the glycolysis pathway. Therefore, our study presents a comprehensive functional encyclopedia of the interactions between EBV antigens and host signaling pathways across various EBV-associated diseases, providing valuable insights for the development of therapeutic strategies. Full article

Approximately 15–20% of global cancer cases are attributed to virus infections. Oncoviruses employ various molecular strategies to enhance replication and persistence. Human cytomegalovirus (HCMV), acting as an initiator or promoter, enables immune evasion, supporting tumor growth. HCMV activates pro-oncogenic pathways within infected cells and direct cellular transformation. Thus, HCMV demonstrates characteristics reminiscent of oncoviruses. Cumulative evidence emphasizes the crucial roles of EZH2 and Myc in oncogenesis and stemness. EZH2 and Myc, pivotal regulators of cellular processes, gain significance in the context of oncoviruses and HCMV infections. This axis becomes a central focus for comprehending the mechanisms driving virus-induced oncogenesis. Elevated EZH2 expression is evident in various cancers, making it a prospective target for cancer therapy. On the other hand, Myc, deregulated in over 50% of human cancers, serves as a potent transcription factor governing cellular processes and contributing to tumorigenesis; Myc activates EZH2 expression and induces global gene expression. The Myc/EZH2 axis plays a critical role in promoting tumor growth in oncoviruses. Considering that HCMV has been shown to manipulate the Myc/EZH2 axis, there is emerging evidence suggesting that HCMV could be regarded as a potential oncovirus due to its ability to exploit this critical pathway implicated in tumorigenesis. Full article

Human cytomegalovirus (HCMV) is a herpesvirus that alternates lytic and latent infection, infecting between 40 and 95% of the population worldwide, usually without symptoms. During its lytic cycle, HCMV can result in fever, asthenia, and, in some cases, can lead to severe symptoms such as hepatitis, pneumonitis, meningitis, retinitis, and severe cytomegalovirus disease, especially in immunocompromised individuals. Usually, the host immune response keeps the virus in a latent stage, although HCMV can reactivate in an inflammatory context, which could result in sequential lytic/latent viral cycles during the lifetime and thereby participate in the HCMV genomic diversity in humans and the high level of HCMV intrahost genomic variability. The oncomodulatory role of HCMV has been reported, where the virus will favor the development and spread of cancerous cells. Recently, an oncogenic role of HCMV has been highlighted in which the virus will directly transform primary cells and might therefore be defined as the eighth human oncovirus. In light of these new findings, it is critical to understand the role of the immune landscape, including the tumor microenvironment present in HCMV-harboring tumors. Finally, the oncomodulatory/oncogenic potential of HCMV could lead to the development of novel adapted therapeutic approaches against HCMV, especially since immunotherapy has revolutionized cancer therapeutic strategies and new therapeutic approaches are actively needed, particularly to fight tumors of poor prognosis. Full article

Chemokines interact with glycosaminoglycans of the extracellular matrix and activate heptahelical cellular receptors that mainly consist of G Protein-Coupled Receptors and a few atypical receptors also with decoy activity. They are well-described targets of oncogenic pathways and key players in cancer development, invasiveness, and metastasis acting both at the level of cancer cells and cells of the tumor microenvironment. Hence, they can regulate cancer cell proliferation and survival and promote immune or endothelial cell migration into the tumor microenvironment. Additionally, oncogenic viruses display the potential of jeopardizing the chemokine system by encoding mimics of chemokines and receptors as well as several products such as oncogenic proteins or microRNAs that deregulate their human host transcriptome. Conversely, the chemokine system participates in the host responses that control the virus life cycle, knowing that most oncoviruses establish asymptomatic latent infections. Therefore, the deregulated expression and function of chemokines and receptors as a consequence of acquired or inherited mutations could bias oncovirus infection toward pro-oncogenic pathways. We here review these different processes and discuss the anticancer therapeutic potential of targeting chemokine availability or receptor activation, from signaling to decoy-associated functions, in combination with immunotherapies. Full article

Fascin is an actin-binding protein that is encoded by the FSCN1 gene (located on chromosome 7). It triggers membrane projections and stimulates cell motility in cancer cells. Fascin overexpression has been described in different types of human cancers in which its expression correlated with tumor growth, migration, invasion, and metastasis. Moreover, overexpression of fascin was found in oncovirus-infected cells, such as human papillomaviruses (HPVs) and Epstein-Barr virus (EBV), disrupting the cell–cell adhesion and enhancing cancer progression. Based on these findings, several studies reported fascin as a potential biomarker and a therapeutic target in various cancers. This review provides a brief overview of the FSCN1 role in various cancers with emphasis on gynecological malignancies. We also discuss fascin interactions with other genes and oncoviruses through which it might induce cancer development and progression. Full article

Cervical cancer is a public health problem and has devastating effects in low-to-middle-income countries (LTMICs) such as the sub-Saharan African (SSA) countries. Infection by the human papillomavirus (HPV) is the main cause of cervical cancer. HIV positive women have higher HPV prevalence and cervical cancer incidence than their HIV negative counterparts do. Concurrent HPV/HIV infection is catastrophic, particularly to African women due to the high prevalence of HIV infections. Although various studies show a relationship between HPV, HIV and cervical cancer, there is still a gap in the knowledge concerning the precise nature of this tripartite association. Firstly, most studies show the relationship between HPV and cervical cancer at genomic and epigenetic levels, while the transcriptomic landscape of this relationship remains to be elucidated. Even though many studies have shown HPV/HIV dual viral pathogenesis, the dual molecular oncoviral effects on the development of cervical cancer remains largely uncertain. Furthermore, the effect of highly active antiretroviral therapy (HAART) on the cellular splicing machinery is unclear. Emerging evidence indicates the vital role played by host splicing events in both HPV and HIV infection in the development and progression to cervical cancer. Therefore, decoding the transcriptome landscape of this tripartite relationship holds promising therapeutic potential. This review will focus on the link between cellular splicing machinery, HPV, HIV infection and the aberrant alternative splicing events that take place in HIV/HPV-associated cervical cancer. Finally, we will investigate how these aberrant splicing events can be targeted for the development of new therapeutic strategies against HPV/HIV-associated cervical cancer. Full article

Besides its well-described impact in immunosuppressed patients, the role of human cytomegalovirus (HCMV) in the pathogenesis of cancer has been more recently investigated. In cancer, HCMV could favor the progression and the spread of the tumor, a paradigm named oncomodulation. Although oncomodulation could account for part of the protumoral effect of HCMV, it might not explain the whole impact of HCMV infection on the tumor and the tumoral microenvironment. On the contrary cases have been reported where HCMV infection slows down the progression and the spread of the tumor. In addition, HCMV proteins have oncogenic properties per se, HCMV activates pro-oncogenic pathways in infected cells, and recently the direct transformation of cells following HCMV infection has been described, which gave rise to tumors when injected in mice. Thus, beyond the oncomodulation model, this review will assess the direct transforming role of HMCV-infected cells and the potential classification of HCMV as an oncovirus. Full article

Oncoviruses are implicated in approximately 12% of all human cancers. A large number of the world’s population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer. The interplay between host and viral factors is a complex process that works together to create a microenvironment conducive to oncogenesis. In this review, the molecular biology and oncogenic pathways of established human oncoviruses will be discussed. Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV). Available and emerging therapies for these oncoviruses will be mentioned. Full article

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders. Full article