Search Results (45)

Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, has been robustly linked to the pathogenesis of nasopharyngeal carcinoma (NPC). The mechanism of EBV-induced NPC involves complex interactions between viral proteins and host cell pathways. This review aims to comprehensively outline the mechanism of EBV-induced NPC and the latest advances in targeted EBV vaccines for prophylaxis and treatment. This review explores the intricate molecular mechanisms by which EBV contributes to NPC pathogenesis, highlighting viral latency, genetic and epigenetic alterations, and immune evasion strategies. It emphasizes the pivotal role of key viral proteins, including EBNA1, LMP1, and LMP2A, in carcinogenesis. Subsequently, the discussion shifts towards the development of targeted EBV vaccines, including preventive vaccines aimed at preventing primary EBV infection and therapeutic vaccines aimed at treating diagnosed EBV-related NPC. The review underscores the challenges and future directions in the field, stressing the importance of developing innovative vaccine strategies and combination therapies to improve efficacy. This review synthesizes current insights into the molecular mechanisms of EBV-induced NPC and the development of EBV-targeted vaccines, highlighting the potential use of mRNA vaccines for NPC treatment. Full article

Background/Objectives: Hepatitis B virus (HBV) infection is a worldwide health problem responsible for chronic liver disease and hepatocellular carcinoma. Both innate immunity and the adaptive immune response play central roles in the development of chronic hepatitis and liver cancer. We previously performed a comprehensive analysis of gene expression in the livers of HBV-infected chimeric mice and found that several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were upregulated by HBV infection. However, due to the absence of adaptive immunity in uPA/SCID chimeric mice, we were unable to analyze the effect of the host immune response. Methods: In this study, we compared gene expression profiles in the livers obtained from HBV-infected chimeric mice with those of HBV carriers. Results: After HBV infection, the expression of genes associated with inflammation and immune response, especially involving the Th1 and Th2 activation pathways, was altered as HBV-specific intracellular immune responses both in vivo and in clinical samples. Interestingly, the proinflammatory gene IL12A was induced by HBV infection in the chimeric mouse livers but not in the human livers, and associated genes, such as SRDA5A2, AR, and CCR3, showed differential alteration by HBV infection between the chimeric mouse and human livers. Conclusions: These results suggest that hepatocarcinogenesis may be suppressed by host immunity in HBV carriers. This study highlights potential new implications for inhibiting the progression of HBV-related liver diseases, including hepatocarcinogenesis. Full article

Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and liver cancer worldwide. Hepatocellular carcinoma (HCC) remains one of the major causes of cancer-related mortality globally. Effective prevention and management strategies for HBV infection are crucial in reducing liver-related complications, including HCC. HBV plays a distinct role in liver carcinogenesis, and there is growing knowledge about the factors contributing to its oncogenic potential. With advancements in HCC management, special attention must be given to the treatment of HBV infection in patients with HBV-induced HCC. In this review, we summarize current insights into the carcinogenic mechanisms of HBV and discuss the latest approaches to managing HBV-induced HCC. Full article

Leukemia is a hematologic malignancy; acute lymphoblastic leukemia (ALL) is the most prevalent subtype among children rather than in adults. Orthoherpesviridae family members produce proteins during latent infection phases that may contribute to cancer development. One such protein, viral interleukin-10 (vIL-10), closely resembles human interleukin-10 (IL-10) in structure. Research has explored the involvement of human cytomegalovirus (hCMV) in the pathogenesis of ALL. However, the limited characterization of its latent-phase proteins restricts a full understanding of the relationship between hCMV infection and leukemia progression. Studies have shown that hCMV induces an inflammatory response during infection, marked by the release of cytokines and chemokines. Inflammation may, therefore, play a role in how hCMV contributes to oncogenesis in pediatric ALL, possibly mediated by latent viral proteins. The classification of a virus as oncogenic is based on its alignment with cancer’s established hallmarks. Viruses can manipulate host cellular mechanisms, causing dysregulated cell proliferation, evasion of apoptosis, and genomic instability. These processes lead to mutations, chromosomal abnormalities, and chronic inflammation, all of which are vital for carcinogenesis. This study aims to investigate the role of vIL-10 during the latent phase of hCMV as a potential factor in leukemia development. Full article

Dysregulated long non-coding RNA (lncRNA) expression is linked to various cancers and may be influenced by oncogenic Epstein–Barr virus (EBV) infection, a known and detectable risk factor in oral squamous cell carcinoma (OSCC) patients. However, research on the oncogenic role of EBV-induced lncRNAs in OSCC is limited. To identify lncRNA-associated EBV infection and OSCC carcinogenesis, the differential expression of RNA-seq datasets from paired normal adjacent and OSCC tissues, and microarray data from EBV-negative and EBV-positive SCC25 cells, were identified and selected, respectively, for interaction, functional analysis, and CCK-8 cell proliferation, wound healing, and invasion Transwell assays. In OSCC tissues, 6731 differentially expressed lncRNAs were identified when compared to normal tissues from RNA-seq datasets, with 295 linked to EBV-induced OSCC carcinogenesis from microarray datasets. The EBV-induced lncRNA VWA8-AS1 showed significant upregulation in EBV-positive SCC25 cells and EBV-infected adjacent and OSCC tissue samples. VWA8-AS1 potentially promotes OSCC via the lncRNA–miRNA–mRNA axis or direct protein interactions, affecting various cellular processes. Studies in OSCC cell lines revealed that elevated VWA8-AS1 levels enhanced cell migration and invasion. This study demonstrates VWA8-AS1’s contribution to tumor progression and possible interactions with its targets in OSCC, offering insights for future research on functional mechanisms and therapeutic targets in EBV-associated OSCC. Full article

The development of keratinocytic skin tumors, presumably attributable to paradoxical activation of the MAPK pathway, represents a relevant side effect of targeted therapies with BRAF inhibitors (BRAFis). The role of cutaneous papillomavirus infection in BRAFi-associated skin carcinogenesis, however, is still inconclusive. Employing the Mus musculus papillomavirus 1 (MmuPV1) skin infection model, the impact of BRAFis and UVB exposure on papillomavirus induced skin tumorigenesis was investigated in immunocompetent FVB/NCrl mice. Systemic BRAF inhibition in combination with UVB light induced skin tumors in 62% of the MmuPV1-infected animals. In contrast, significantly fewer tumors were observed in the absence of either BRAF inhibition, UVB irradiation or virus infection, as demonstrated by lesional outgrowth in 20%, 5% and 0% of the mice, respectively. Combinatory exposure to BRAFis and UVB favored productive viral infection, which was shown by high numbers of MmuPV1 genome copies and E1^E4 spliced transcripts and an abundance of E6/E7 oncogene mRNA and viral capsid proteins. BRAF inhibition, but not viral infection or UVB light, activated ERK1/2, whereas γH2AX expression, inducible by UVB light, remained unaltered by BRAFis. These results provide experimental evidence that BRAF inhibition and UVB irradiation synergistically promote MmuPV1-induced skin tumor development in vivo. This indicates an alternative pathway by which papillomavirus skin infection may contribute to BRAFi-associated skin tumorigenesis. Full article

Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting “epigenetic memory”, suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC. Full article

Recent studies have shown that thyrocytes are permissive to HHV-6A infection and that the virus may contribute to the pathogenesis of autoimmune thyroiditis. Thyroid autoimmune diseases increase the risk of papillary cancer, which is not surprising considering that chronic inflammation activates pathways that are also pro-oncogenic. Moreover, in this condition, cell proliferation is stimulated as an attempt to repair tissue damage caused by the inflammatory process. Interestingly, it has been reported that the well-differentiated papillary thyroid carcinoma (PTC), the less aggressive form of thyroid tumor, may progress to the more aggressive follicular thyroid carcinoma (FTC) and eventually to the anaplastic thyroid carcinoma (ATC), and that to such progression contributes the presence of an inflammatory/immune suppressive tumor microenvironment. In this study, we investigated whether papillary tumor cells (BCPAP) could be infected by human herpes virus-6A (HHV-6A), and if viral infection could induce effects related to cancer progression. We found that the virus dysregulated the expression of several microRNAs, such as miR-155, miR-9, and the miR-221/222 cluster, which are involved in different steps of carcinogenesis, and increased the secretion of pro-inflammatory cytokines, particularly IL-6, which may also sustain thyroid tumor cell growth and promote cancer progression. Genomic instability and the expression of PTEN, reported to act as an oncogene in mutp53-carrying cells such as BCPAP, also increased following HHV-6A-infection. These findings suggest that a ubiquitous herpesvirus such as HHV-6A, which displays a marked tropism for thyrocytes, could be involved in the progression of PTC towards more aggressive forms of thyroid tumor. Full article

Chronic inflammation is linked to carcinogenesis, particularly in the digestive organs, i.e., the stomach, colon, and liver. The mechanism of this effect has, however, only partly been focused on. In this review, we focus on different forms of chronic hepatitis, chronic inflammatory bowel disease, and chronic gastritis, conditions predisposing individuals to the development of malignancy. Chronic inflammation may cause malignancy because (1) the cause of the chronic inflammation is itself genotoxic, (2) substances released from the inflammatory cells may be genotoxic, (3) the cell death induced by the inflammation induces a compensatory increase in proliferation with an inherent risk of mutation, (4) changes in cell composition due to inflammation may modify function, resulting in hormonal disturbances affecting cellular proliferation. The present review focuses on chronic gastritis (Helicobacter pylori or autoimmune type) since all four mechanisms may be relevant to this condition. Genotoxicity due to the hepatitis B virus is an important factor in hepatocellular cancer and viral infection can similarly be central in the etiology and malignancy of inflammatory bowel diseases. Helicobacter pylori (H. pylori) is the dominating cause of chronic gastritis and has not been shown to be genotoxic, so its carcinogenic effect is most probably due to the induction of atrophic oxyntic gastritis leading to hypergastrinemia. Full article

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors worldwide that poses a significant threat to human health. The multifunctional regulator known as Hepatitis B virus X-protein (HBx) interacts with host factors, modulating gene transcription and signaling pathways and contributing to hepatocellular carcinogenesis. The p90 ribosomal S6 kinase 2 (RSK2) is a member of the 90 kDa ribosomal S6 kinase family involved in various intracellular processes and cancer pathogenesis. At present, the role and mechanism of RSK2 in the development of HBx-induced HCC are not yet clear. In this study, we found that HBx upregulates the expression of RSK2 in HBV-HCC tissues, HepG2, and SMMC-7721 cells. We further observed that reducing the expression of RSK2 inhibited HCC cell proliferation. In HCC cell lines with stable HBx expression, RSK2 knockdown impaired the ability of HBx to promote cell proliferation. The extracellularly regulated protein kinases (ERK) 1/2 signaling pathway, rather than the p38 signaling pathway, mediated HBx-induced upregulation of RSK2 expression. Additionally, RSK2 and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were highly expressed and positively correlated in HBV-HCC tissues and associated with tumor size. This study showed that HBx upregulates the expression of RSK2 and CREB by activating the ERK1/2 signaling pathway, promoting the proliferation of HCC cells. Furthermore, we identified RSK2 and CREB as potential prognostic markers for HCC patients. Full article

Human papillomavirus (HPV) is a group of alpha papillomaviruses that cause various illnesses, including cancer. There are more than 160 types of HPV, with many being “high-risk” types that have been clinically linked to cervical and other types of cancer. “Low-risk” types of HPV cause less severe conditions, such as genital warts. Over the past few decades, numerous studies have shed light on how HPV induces carcinogenesis. The HPV genome is a circular double-stranded DNA molecule that is approximately 8 kilobases in size. Replication of this genome is strictly regulated and requires two virus-encoded proteins, E1 and E2. E1 is a DNA helicase that is necessary for replisome assembly and replication of the HPV genome. On the other hand, E2 is responsible for initiating DNA replication and regulating the transcription of HPV-encoded genes, most importantly the E6 and E7 oncogenes. This article explores the genetic characteristics of high-risk HPV types, the roles of HPV-encoded proteins in HPV DNA replication, the regulation of transcription of E6 and E7 oncogenes, and the development of oncogenesis. Full article

Chemical, physical, and infectious agents may induce carcinogenesis, and in the latter case, viruses are involved in most cases. The occurrence of virus-induced carcinogenesis is a complex process caused by an interaction across multiple genes, mainly depending by the type of the virus. Molecular mechanisms at the basis of viral carcinogenesis, mainly suggest the involvement of a dysregulation of the cell cycle. Among the virus-inducing carcinogenesis, Epstein Barr Virus (EBV) plays a major role in the development of both hematological and oncological malignancies and importantly, several lines of evidence demonstrated that nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection. Cancerogenesis in NPC may be induced by the activation of different EBV “oncoproteins” which are produced during the so called “latency phase” of EBV in the host cells. Moreover, EBV presence in NPC does affect the tumor microenvironment (TME) leading to a strongly immunosuppressed status. Translational implications of the above-mentioned statements are that EBV-infected NPC cells can express proteins potentially recognized by immune cells in order to elicit a host immune response (tumor associated antigens). Three immunotherapeutic approaches have been implemented for the treatment of NPC including active, adoptive immunotherapy, and modulation of immune regulatory molecules by use of the so-called checkpoint inhibitors. In this review, we will highlight the role of EBV infection in NPC development and analyze its possible implications on therapy strategies. Full article

Cervical cancer is the eighth most frequent cancer in Saudi Arabia, and most cases are associated with human papillomavirus (HPV) types 16 and 18. HPV-induced carcinogenesis may be associated with the intra-type variant, genetic mutation, or the continuous expression of viral oncogenes E6 and E7. Infection efficiency and virus antigenicity may be affected by changes in the L1 gene. Thus, this retrospective cohort study analyzed E6, E7, and L1 gene mutations in cervical specimens collected from Saudi women positive for HPV16 or HPV18 infection. HPV16 and HPV18 lineages in these specimens were predominantly from Europe. The L83V mutation in the E6 gene of HPV16 showed sufficient oncogenic potential for progression to cervical cancer. By contrast, the L28F mutation in the E7 gene of HPV16 was associated with a low risk of cervical cancer. Other specific HPV16 and HPV18 mutations were associated with an increased risk of cancer, cancer progression, viral load, and age. Four novel mutations, K53T, K53N, R365P, and K443N, were identified in the L1 gene of HPV16. These findings for HPV16 and HPV18 lineages and mutations in the E6, E7, and L1 genes among women in Saudi Arabia may inform the design and development of effective molecular diagnostic tests and vaccination strategies for the Saudi population. Full article

Reprogrammed metabolism is regarded as a hallmark of cancer and offers a selective advantage to tumor cells during carcinogenesis. The redox equilibrium is necessary for growth, spread and the antioxidant pathways are boosted following Reactive Oxygen Species (ROS) production to prevent cell damage in tumor cells. Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi sarcoma KS and primary effusion lymphoma (PEL), is an oncogenic virus that disrupts cell survival-related molecular signaling pathways leading to immune host evasion, cells growths, angiogenesis and inflammatory tumor-environment. We recently reported that primaquine diphosphate causes cell death by apoptosis in HHV-8 infected PEL cell lines in vivo and exhibits therapeutic anti-tumor activity in mice models and advanced KS. Our findings also suggest that the primaquine-induced apoptosis in PEL cells is mostly influenced by ROS production and targeting the redox balance could be a new approach to treat HHV-8 related diseases. In this review, we summarized the knowledge about the influence of ROS in cancer development; more specifically, the proof of evidence from our work and from the literature that redox pathways are important for the development of HHV-8 pathologies. Full article

Cancer induced by a viral infection is among the leading causes of cancer. Hepatitis C Virus (HCV) is a hepatotropic oncogenic positive-sense RNA virus that leads to chronic infection, exposing the liver to a continuous process of damage and regeneration and promoting hepatocarcinogenesis. The virus promotes the development of carcinogenesis through indirect and direct molecular mechanisms such as chronic inflammation, oxidative stress, steatosis, genetic alterations, epithelial-mesenchymal transition, proliferation, and apoptosis, among others. Recently, direct-acting antivirals (DAAs) showed sustained virologic response in 95% of cases. Nevertheless, patients treated with DAAs have reported an unexpected increase in the early incidence of Hepatocellular carcinoma (HCC). Studies suggest that HCV induces epigenetic regulation through non-coding RNAs, DNA methylation, and chromatin remodeling, which modify gene expressions and induce genomic instability related to HCC development that persists with the infection’s clearance. The need for a better understanding of the molecular mechanisms associated with the development of carcinogenesis is evident. The aim of this review was to unravel the molecular pathways involved in the development of carcinogenesis before, during, and after the viral infection’s resolution, and how these pathways were regulated by the virus, to find control points that can be used as potential therapeutic targets. Full article