Herpesvirus ubiquitin deconjugases.

The covalent attachment of ubiquitin and ubiquitin-like polypeptides to cellular and viral proteins regulates numerous processes that enable virus infection, viral genome replication, and the spread of viruses to new hosts. The importance of these protein modifications in the regulation of the life cycle of herpesviruses is underscored by the discovery that all known members of this virus family encode at least one protease that specifically recognizes and disassembles ubiquitin conjugates. The structural and functional characterization of the viral enzymes and the identification of their viral and cellular substrates is providing valuable insights into the biology of viral infection and increasing evidence suggests that the viral deconjugases may also play a role in malignant transformation.

Eph receptors: the bridge linking host and virus.

Eph (erythropoietin-producing hepatoma) receptors and Ephrin ligands constitute the largest subfamily of receptor tyrosine kinase (RTK), which were first discovered in tumors. Heretofore, Eph protein has been shown to be involved in various tumor biological behaviors including proliferation and progression. The occurrence of specific types of tumor is closely related to the virus infection. Virus entry is a complex process characterized by a series of events. The entry into target cells is an essential step for virus to cause diseases, which requires the fusion of the viral envelope and host cellular membrane mediated by viral glycoproteins and cellular receptors. Integrin molecules are well known as entry receptors for most herpes viruses. However, in recent years, Eph receptors and their Ephrin ligands have been reported to be involved in virus infections. The main mechanism may be the interaction between Eph receptors and conserved viral surface glycoprotein, such as the gH/gL or gB protein of the herpesviridae. This review focuses on the relationship between Eph receptor family and virus infection that summarize the processes of viruses such as EBV, KSHV, HCV, RRV, etc., infecting target cells through Eph receptors and activating its downstream signaling pathways resulting in malignancies. Finally, we discussed the perspectives to block virus infection, prevention, and treatment of viral-related tumors via Eph receptor family.

Interplay between viruses and bacterial microbiota in cancer development.

During the last few decades we have become accustomed to the idea that viruses can cause tumors. It is much less considered and discussed, however, that most people infected with oncoviruses will never develop cancer. Therefore, the genetic and environmental factors that tip the scales from clearance of viral infection to development of cancer are currently an area of active investigation. Microbiota has recently emerged as a potentially critical factor that would affect this balance by increasing or decreasing the ability of viral infection to promote carcinogenesis. In this review, we provide a model of microbiome contribution to the development of oncogenic viral infections and viral associated cancers, give examples of this process in human tumors, and describe the challenges that prevent progress in the field as well as their potential solutions.

Risk of virus-associated cancer in female arthritis patients treated with biological DMARDs-a cohort study.

OBJECTIVE: To investigate the risk of virus-associated cancer in female arthritis patients ever treated with biological DMARDs (bDMARDs) compared with never bDMARD-treated patients and ever and never treated with bDMARD compared with the general population. METHODS: This was a cohort study that included 13 905 female patients with RA (72%), PsA (12%), AS (4%) or other arthritides (12%) identified in the DANBIO registry. Ever (n = 5647) and never (n = 10 331) bDMARD-treated patients were followed for virus-associated cancers during 2000-11 by linkage to the Danish Cancer Registry. Hazard ratios and standardized incidence ratios (SIRs) were calculated. RESULTS: In total, 24 and 32 virus-associated cancers were identified among ever and never bDMARD users, respectively (hazard ratio = 0.9, 95% CI: 0.7, 1.2). Oropharyngeal (n = 3, SIR = 4.0, 95% CI: 1.3, 12.4) and anal (n = 2, SIR = 2.5, 95% CI: 0.6, 10.0) cancer only occurred among bDMARD-treated patients. SIR was not increased for cervical cancer, either in ever or never bDMARD-treated patients. SIRs for Hodgkin's and non-Hodgkin's lymphomas were increased in never bDMARD-treated patients (SIR = 2.5, 95% CI: 1.5, 4.0). CONCLUSION: bDMARD therapy was not associated with an overall excess of virus-associated cancers in female arthritis patients. The observed increased occurrence of oropharyngeal cancer needs further investigation. Lymphoma incidence was increased in patients unexposed to bDMARD treatment.

Small extracellular vesicles as key players in cancer development caused by human oncogenic viruses.

BACKGROUND: Exosomes are the smallest group of extracellular vesicles in size from 30 to 150 nm, surrounded by a lipid bilayer membrane, and originate from multivesicular bodies secreted by different types of cells, such as virus-infected cells. The critical role of exosomes is information transfer among cells, representing a unique way for intercellular communication via a load of many kinds of molecules, including various signaling proteins and nucleic acids. In this review, we aimed to comprehensively investigate the role of exosomes in promoting human oncogenic viruses-associated cancers. METHODS: Our search was conducted for published researches between 2000 and 2022 by using several international databases includeing Scopus, PubMed, and Web of Science as well as Google scholar. We also reviewed additional evidence from relevant published articles. RESULTS: It has been shown that exosomes can create the conditions for viral spread in viral infections. Exosome secretion in a human tumor virus can switch on the cell signaling pathways by transferring exosome-encapsulated molecules, including viral oncoproteins, signal transduction molecules, and virus-encoded miRNAs, into various cells. CONCLUSION: Given the role of exosomes in viruses-associated cancers, they can also be considered as molecular targets in diagnosis and treatment.

RNA Sequencing and Cell Models of Virus-Associated Cancer (Review).

The review summarizes findings from the studies based on the application of technologies for transcriptome analysis to modern cellular model systems of human papillomavirus-associated cancer (HPV) (cervical cancer, head and neck tumors). A diversity of three-dimensional cancer models, such as spheroids, organoids (organotypic cultures), explants, mouse xenografts, are addressed. Particular attention is paid to the use of patient-derived biomaterial for establishing short-term cultures of primary tumor cells, as well as generating multicomponent (heterocellular) systems that comprise, together with the tumor component, other elements of its microenvironment. A number of unique biological properties of HPV-induced neoplasia are discussed, which make generating cell models a unique task. The novel findings in the field of molecular mechanisms of the onset and progression of HPV-associated cancer achieved by using RNA sequencing are presented for each variant of the model systems. These findings are considered in regard to applied aspects of their use, in terms of the opportunities for preclinical testing of new drugs, personalized diagnostics and selection of individual, most effective treatment regimens. The issues of drug resistance development, molecular-cellular heterogeneity, epigenetic reprogramming, and the role of the stromal microenvironment are reviewed. The paper accentuates the problems related to the limitations of the applicability of a particular model system. The areas with a significant lagging behind in omics research of virus-associated cancer in comparison with other types of oncological pathology and possible causes of this lag are noted. The future prospects for the development of model systems of HPV-associated tumors in the field of high-tech tissue engineering, in particular, the use of bioprinting and microfluidic biochips, are also outlined. The combination of these techniques with the methods of whole genome profiling will significantly increase the translational potential of the described model cell systems.

Exosomes in virus-associated cancer.

Exosomes are phospholipid bilayer membrane-enclosed vesicles in a size from 30 to 150 nm, carrying a variety of active components, such as proteins, mRNA and miRNAs, and are involved in intercellular communication. Exosomes are released by almost all living cells and detected in various biological fluids. Viruses especially oncogenic viruses have been reported to influence the formation of virus-associated cancer through reshaping the tumor microenvironment via exosomes. In this review, a role of exosomes released by oncogenic virus-infected cells in promoting or inhibiting cancer formation is outlined. Moreover, the prospects and challenges of exosome applications in cancer therapies are critically discussed.

The 150 most important questions in cancer research and clinical oncology series: questions 86-93 : Edited by Chinese Journal of Cancer.

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which spark diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, 8 more questions are presented as follows. Question 86. In which circumstances is good supportive care associated with a survival advantage in patients with cancer? Question 87. Can we develop animal models to mimic immunotherapy response of cancer patients? Question 88. What are the mechanisms underlying hepatitis B virus-associated non-hepatocellular cancers? Question 89. Can we more precisely target tumor metabolism by identifying individual patients who would benefit from the treatment? Question 90. What type of cranial irradiation-based prophylactic therapy combination can dramatically improve the survival of patients with extensive small-cell lung cancer? Question 91. How can postoperative radiotherapy prolong overall survival of the patients with resected pIIIA-N2 non-small cell lung cancer? Question 92. What are the key molecular events that drive oral leukoplakia or erythroplakia into oral cancer? Question 93. How could we track the chemotherapeutics-driven evolution of tumor genome in non-small cell lung cancer for more effective treatment?

The 150 most important questions in cancer research and clinical oncology series: questions 86-93 : Edited by Chinese Journal of Cancer / 癌症

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which spark diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, 8 more questions are presented as follows. Question 86. In which circumstances is good supportive care associated with a survival advantage in patients with cancer? Question 87. Can we develop animal models to mimic immunotherapy response of cancer patients? Question 88. What are the mechanisms underlying hepatitis B virus-associated non-hepatocellular cancers? Question 89. Can we more precisely target tumor metabolism by identifying individual patients who would benefit from the treatment? Question 90. What type of cranial irradiation-based prophylactic therapy combination can dramatically improve the survival of patients with extensive small-cell lung cancer? Question 91. How can postoperative radiotherapy prolong overall survival of the patients with resected pIIIA-N2 non-small cell lung cancer? Question 92. What are the key molecular events that drive oral leukoplakia or erythroplakia into oral cancer? Question 93. How could we track the chemotherapeutics-driven evolution of tumor genome in non-small cell lung cancer for more effective treatment?

Human MHC Class I-restricted high avidity CD4+ T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo.

In this study, we generated human MHC Class I-restricted CD4+ T cells specific for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), two herpesviridae associated with lymphoma, nasopharyngeal carcinoma and medulloblastoma, respectively. Retroviral transfer of virus-specific, HLA-A2-restricted TCR-coding genes generated CD4+ T cells that recognized HLA-A2/peptide multimers and produced cytokines when stimulated with MHC Class II-deficient cells presenting the relevant viral peptides in the context of HLA-A2. Peptide titration revealed that CD4+ T cells had a 10-fold lower avidity than CD8+ T cells expressing the same TCR. The impaired avidity of CD4+ T cells was corrected by simultaneously transferring TCR- and CD8-coding genes. The CD8 co-receptor did not alter the cytokine signature of CD4+ T cells, which remained distinct from that of CD8+ T cells. Using the xenogeneic NOD/SCID mouse model, we demonstrated that human CD4+ T cells expressing a specific TCR and CD8 can confer efficient protection against the growth of tumors expressing the EBV or CMV antigens recognized by the TCR. In summary, we describe a robust approach for generating therapeutic CD4+ T cells capable of providing MHC Class I-restricted immunity against MHC Class II-negative tumors in vivo.