Grand: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK. Stonehouse: School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Center for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Human Viruses and Cancer
Introduction: Historical and Epidemiological Aspects
The disease must exist in the same space with the agent, preferably over other associations of the same agent and another disease. This strongly supports that the virus was part of the initial genetic lesion that enabled the appearance of the cancerous clone, and met the Bradford Hill criteria for transience.
General Principles of Viral Oncogenic Mechanisms
For example, EBV is found in B-lymphocytes that are reactivated in the epithelium of the upper digestive tract, and EBV has been associated with B-cell lymphomas and carcinomas of the tongue, nasopharynx, and stomach. Retroviruses whose replication cycle requires integration of the viral genome into the host genome are commonly transformed because integration deregulates expression of cellular oncogenes or tumor suppressor genes (insertional mutagenesis, see Section 4.2).
Human Oncogenic Viruses and Associated Cancers
A key event in the oncogenic process is the integration of the viral genome, a step that usually results in loss of E2 and overexpression of E6 and E7 (reviewed in [60]). This is a significant difference between the presence of the virus in MCC and in non-tumor tissue.
Common Mechanisms of Direct Carcinogenesis 1. Viral Oncogenes and Oncoproteins
How tumor viruses regulate telomere length is not clear, but HPV E6, EBV LMP1, KSHV LANA, HTLV1 Tax and HBV HBx have all been shown to induce expression of telomerase [144–147]. Therefore, integration correlates with the establishment of a latent stage, overexpression of viral oncogenes, and host cell transformation (see Sections 3.2 and 3.3).
Common Mechanisms of Indirect Carcinogenesis
Persistent infection is generally accompanied by local chronic inflammation, with immune response evasive mechanisms still present. The role of the immune system in onco-surveillance has been well established since the AIDS pandemic.
Conclusions
Expression of epstein-barr virus latent membrane protein 1 induces b-cell lymphoma in transgenic mice. Qualitative analysis of the expression of epstein-barr virus lytic genes in nasopharyngeal carcinoma biopsies.
The Role of Merkel Cell Polyomavirus and Other Human Polyomaviruses in Emerging Hallmarks of Cancer
Introduction
Raccoon polyomavirus (RacPyV) was first identified in tumors of frontal lobes and olfactory tracts of raccoons. A polyomavirus was isolated from fibropapilloma on the tongue of a sea lion, and the entire genome of another polyomavirus was amplified in a biopsy from a fibroma on the trunk of an African elephant [16,17].
Human Polyomaviruses and Cancer
This virus, Simian virus 40 (SV40), has been shown to transform cells, including human cells, to induce tumors in animal models and to be involved in human cancer. Whether these viruses can be detected in human colorectal biopsies remains to be determined.
HPyV and Emerging Hallmarks of Cancer 1. The Immune System and HPyV in Cancer
Immune cells and inflammatory mediators in MCPyV-positive and MCPyV-negative Merkel cell carcinoma (MCC). These analyzes showed that MHC-I expression was significantly lower in MCPyV-positive MCC than in virus-negative MCC [96].
Therapeutic Strategies against Emerging Hallmarks of Cancer
Exosomes released from virus-infected cells may also contain viral-derived components and are implicated in the pathogenesis of viruses. They can induce host immune and inflammatory responses by activating T- and B-cells, and releasing exosome-entrapped inflammatory molecules such as TNFĮ and IL1ȕ into recipient cells.
Conclusion and Future Perspectives
Screening of the specific polyoma virus as diagnostic and prognostic tools for Merkel cell carcinoma. Merkel cell polyomavirus-positive Merkel cell carcinoma cells do not require expression of the viral small T antigen. Tissue site-specific enhancer function of the upstream regulatory region of human papillomavirus type 11 in cultured keratinocytes.J.
Stem cells in the hair follicle bulge contribute to wound repair, but not to homeostasis of the epidermis. Eccrine-centered distribution of human papillomavirus 63 infection in the epidermis of the plantar skin.Br.
Human Papillomavirus and Tonsillar and Base of Tongue Cancer
- Human Papillomavirus (HPV) and Disease and Cancer
- TSCC, BOTSCC and HPV and Its Influence on Clinical Outcome and Number of Cases OSCC includes not only TSCC and BOTSCC, which accounting for 80% of the cases, but also
- TSCC, BOTSCC, HPV and Other Biomarkers and Treatment
- Prevention of HPV-Positive TSCC and BOTSCC
Prevalence of human papillomavirus and survival in oropharyngeal cancer other than tonsil or base of tongue cancer. Correlation of lmp10 expression and clinical outcome in human papillomavirus (HPV) positive and HPV negative tonsillar and base of tongue cancer. Hla-a*02 in relation to outcome in human papillomavirus-positive tonsillar and base of tongue cancer.
Interaction of Human Tumor Viruses with Host Cell Surface Receptors and Cell Entry
Epstein-Barr Virus
The initial binding of EBV to either the B cell or the epithelial cell membrane eventually causes fusion with the EBV envelope which is considered the second stage of the infection process. While infection of B cells occurs primarily via endocytosis followed by fusion of the virus envelope with the endocytic vesicle membrane, epithelial cells generally enter through direct fusion with the host cell's plasma membrane at the cell surface [15]. In B lymphocytes, EBV was found to use the host cell surface human leukocyte antigen class II (HLA class II) through binding to the viral glycoprotein gp42 which binds non-covalently to the gH-gL fusion machinery complex and GB.
Kaposi’s Sarcoma-Associated Herpes Virus
This interaction eventually causes the fusion of the virus with the endosomal membrane, allowing entry of the tegumented capsid into the cytoplasm [ 16 ]. EBV fusion with the plasma membrane and entry into epithelial cells has recently been shown to involve neuropilin 1 (NRP1) which directly interacts with gB [9], as well as binding of gH-gL to integrins αVβ6 and αVβ8 [18] via recruitment and receptor tyrosine kinase activation and signaling via epidermal growth factor receptor (EGFR)/Akt and EGFR/extracellular signal-regulated kinases (ERK) [ 9 ]. At the initial stage of infectious cell entry, KSHV attaches to host cell surface HSPGs primarily via gB and gpK8.1A [35,37], possibly followed by conformational changes in viral glycoproteins that allow access to specific entry receptors that function in the second phase of infection [38].
Human Papillomavirus
Downstream of the described surface-mediated events, KSHV infection has been found to depend on the activation of focal adhesion kinase (FAK) [50], phosphorylated Src [51] and phosphoinositide 3-kinase (PI3K) signaling [52]. Viral infection predominantly occurs in the mitotically active basal layer of keratinocytes attached to the basement membrane of the host's skin and mucosal epithelium. Conformational changes in the virus capsid are thought to be induced by cyclophilin B [68], thereby increasing the exposure of the otherwise hidden amino terminus of the L2 protein, which contains a highly conserved consensus site for the proprotein convertase furin.
Merkel Cell Polyomavirus
The MCPyV capsid consists of the structural proteins VP1 and VP2 in a ratio of 5:2 for native virions, while the VP3 minor capsid protein found in other polyomaviruses is undetectable in MCPyV [91,111]. Essential for MCPyV entry are pentameric knobs consisting of the major capsid protein VP1 that binds to cellular receptors [112]. This sialic acid binding site differs from that of the previously characterized polyomaviruses BKPyV and murine polyomavirus for which sialylated glycans are primary attachment receptors and which differs from the yet unidentified binding site for sulfated glycosaminoglycans [112].
Hepatitis B Virus
The N-terminal preS1 domain of the L-protein is myristoylated at glycine 2, and this post-translational modification has been shown to be essential for viral infectivity [127–129]. HBV uptake into hepatocytes is thought to be regulated by clathrin-mediated endocytosis of the NTCP-HBV complex. HBV L-protein PreS1 interacts with the clathrin heavy chain and the clathrin adapter protein AP-2.
Hepatitis C Virus
The virus can initiate infection of the host cell as a cell-free particle and/or via cell-cell contact [147]. However, the initial binding and concentration of the virus to the hepatocyte surface is similar for both HBV and HCV and occurs via HSPGs, which are mediated by the HCV glycoprotein E2 and host ApoE present in the viral envelope [136,150]. It is hypothesized that the lipid-rich nature of the HCV particle may favor an initial interaction with SR-B1, possibly leading to conformational changes in the HCV glycoproteins [153], thereby contributing to HCV entry into a High Density Lipoprotein (HDL )-dependent manner [154,155].
Human T Cell Lymphotropic Virus Type 1
Amino acid residues in the RBD of gp46 that are essential for GLUT-1 binding have been shown to differ from the NRP1 and HSPG binding sites, suggesting the formation of a multireceptor complex [193,197]. MTOC polarization is promoted by the interaction of intercellular adhesion molecule-1 or -3 (ICAM-1, ICAM-3) or vascular cell adhesion molecule-1 (VCAM-1) on infected cells with β-integrins, such as a lymphocyte. with function-associated antigen-1 (LFA-1) on uninfected cells [199–201]. NRP1 and GLUT-1 have been shown to localize at the contact point and putatively promote VS formation [193,202], which is also facilitated by the HTLV-1-encoded transcriptional transactivator protein Tax (transcriptional activator of the pX region) [203].
Conclusion
The role of heparan sulfate in human papillomavirus binding and infection of the genital tract of female mice. Human papillomavirus type 16 cell entry involves activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway and inhibition of autophagy. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of L1 and L2 capsid proteins.J.
Role of heparan sulfate in association with and infection of the murine female genital tract with human papillomavirus.J. Cyclophilins facilitate dissociation of the human papillomavirus type 16 capsid protein L1 from the L2/DNA complex after virus entry.J.
High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling
Viral Recognition by Keratinocytes
Basal KCs express pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RNA helicases, to recognize pathogen-associated molecular patterns (PAMPs) on viruses and microbes. The expression of TLR4 and TLR9 in basal KCs is still under debate, but TLR9 expression can be induced after terminal differentiation [17]. Whether HPV disrupts the expression of TLRs, RIG-I or MDA5 in HPV episome-containing KCs is still under debate [17,18,22].
HPV Influences Innate Immune Signaling
STAT1 homo-dimers translocate to the nucleus and bind to γ-activated sequences (GAS) on the DNA, thereby activating ISG transcription more associated with IFNγ signaling (Figure 2) [26,37]. Activated STAT1 can also homodimerize, translocate to the nucleus, bind to GAS, and initiate ISG transcription. In the nucleus, NFκB binds to the DNA and is assisted by coactivators to initiate gene transcription.
The Action of KCs to Secondary Immune Signals is Suppressed by HPV
This induces SCF-βTrCP to ubiquitinate p100 with a K48-linked poly-ubiquitin chain, leading to proteosomal processing of p100 to p52 and subsequent nuclear translocation of the p52-RelB dimer (Figure 3). Furthermore, E6 binds to the C-terminus of TNFR1 [65], and the N-terminus of the death effector domains (DEDs) of FADD, which accelerates the degradation of FADD [66], thereby inhibiting the induction of apoptosis. Furthermore, E7 binds to the IKK complex and attenuates the TNFα-induced kinase activity of IKKα and IKKβ, which inhibits the phosphorylation and degradation of IκBα, and the subsequent nuclear translocation of NFκB [ 48 ].
HrHPV Influences MHC Surface Expression and Peptide Presentation
HPV proteins (red) attenuate gene expression of critical components of this pathway and also actively retain MHC-I in the ER and Golgi apparatus. The complex travels via the ER and Golgi apparatus to lysosomes, where the invariant chain is degraded and MHC-II loaded with processed peptides from endocytosed proteins. Upon IFNγ stimulation, HPV E5 (red) blocks invariant chain degradation and peptide loading and inhibits endosome acidification and maturation.
Final Comments
The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter. Human papillomavirus type 16 E5 protein induces beta interferon expression through interferon regulatory factor 1 in human keratinocytes. The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation of CBP and p300.
Modulation of DNA Damage and Repair Pathways by Human Tumour Viruses
Human Tumour Viruses
It is now clear that only in relatively rare cases do oncogenic viruses in isolation give rise to tumors in otherwise healthy individuals. For example, while the majority of the population carries latent persistent EBV infection, EBV-derived tumors are relatively rare. As outlined here, it is likely that genomic instability induced during the viral life cycle plays a significant role in tumor initiation.
The DNA Damage Response (DDR)
The phosphorylation of the Cdc25 phosphatases leads to their degradation, which prevents the activation of cyclin-dependent kinases (CDKs) that cause cell cycle retardation. In addition, activation of the tyrosine kinase Wee1 after DNA damage leads to inhibition of the cyclin B/Cdk1 complex, preventing the G2/M transition. Sustained activation of the DDR can also lead to cellular aging, where the cell remains viable but replication capacity is lost.
