Special Issue "DNA Viruses in Human Cancer"

Quicklinks

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2014)

Special Issue Editor

Guest Editor
Dr. Elena Kashuba

Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Box 280, S-171 77, Stockholm, Sweden
Website | E-Mail
Phone: +46852486767
Fax: +46 8 33 04 98
Interests: cell transformation; virus-induced cell transformation; Epstein-Barr virus; protein–protein interaction; cell cycle regulation; tumor cell metabolism; nuclear receptors; mitochondrial ribosomal protein S18-2; cell differentiation, cancerogenesis

Special Issue Information

Dear Colleague,

As you are well aware, DNA tumor viruses normally induce an S-phase in the natural host cell which is linked with cell transformation. In the case of small and medium sized DNA tumor viruses (Simian virus 40 (SV40), polyoma, and transforming adenoviruses) the induction of the S-phase is associated with the inactivation of the RB and the p53 pathways. Human papillomavirus, for example, encodes the E6 antigen that binds to p53 and to the cellular ubiquitin-protein ligase, E3A (UBE3A), also known as E6-associated protein. This binding leads to polyubiquitination of p53 and its proteasomal degradation. Large T encoded by SV40 binds to the DNA-binding domain of p53, and also to RB, and inhibits their functional activity.

In the much larger and more complex herpesviruses, this is not so straightforward. For example, ORF72 of human herpesvirus 8 (Kaposi’s sarcoma herpesvirus, KSHV) encodes a cyclin, homologous to cyclin D2, that binds to cdk6. This leads to the phosphorylation of RB and release of E2F1. The transactivating activity of p53 is blocked by KSHV-encoded LANA protein and the functionally corresponding ORF73 of Herpesvirus saimiri.

Epstein-Barr virus (EBV) is a human gamma herpesvirus that immortalizes B-cells. Six EBV-encoded nuclear antigens (EBNAs) and three latent membrane proteins (LMPs) constitute the growth transformation program III (also called latency III), that is not used in non-B-cells. Although the mechanism of EBV-induced B-cell transformation is not fully understood, it is already apparent that the virus exploits the normal signaling pathways of the B-lymphocyte. The growth transformation-associated viral proteins promote cell proliferation and protect the cells from apoptosis.

In this Special Issue of Cancers, “DNA viruses in human cancer”, experts are invited to contribute original research papers or review articles that will provide further insights on the role of DNA tumor viruses in cancerogenesis.

Dr. Elena Kashuba
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).


Keywords

  • DNA tumor virus
  • Epstein-Barr virus
  • cell transformation
  • tumorigenesis
  • oncogene
  • tumor suppressor gene
  • cell proliferation
  • apoptosis
  • cell metabolism
  • cell signaling
  • protein–protein interaction

Published Papers (11 papers)

View options order results:
result details:
Displaying articles 1-11
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle From Human Papillomavirus (HPV) Detection to Cervical Cancer Prevention in Clinical Practice
Cancers 2014, 6(4), 2072-2099; doi:10.3390/cancers6042072
Received: 4 May 2014 / Revised: 25 September 2014 / Accepted: 25 September 2014 / Published: 2 October 2014
Cited by 6 | PDF Full-text (1124 KB) | HTML Full-text | XML Full-text
Abstract
The newly gained knowledge of the viral etiology in cervical carcinogenesis has prompted industrial interests in developing virology-based tools for cervical cancer prevention. Due to the long incubation period from viral infection to developing an invasive cancer, a process whose outcome is influenced
[...] Read more.
The newly gained knowledge of the viral etiology in cervical carcinogenesis has prompted industrial interests in developing virology-based tools for cervical cancer prevention. Due to the long incubation period from viral infection to developing an invasive cancer, a process whose outcome is influenced by numerous life-style and genetic factors, the true efficacy of the genotype-specific human papillomavirus (HPV) vaccines in cervical cancer prevention cannot be determined for another 30 years. Most HPV DNA test kits designed to replace the traditional Papanicolaou (Pap) smears for precancer detection lack the analytical sensitivity and specificity to comprehensively detect all potentially carcinogenic HPVs and to perform reliable genotyping. The authors implemented the classic nested PCR and Sanger DNA-sequencing technology for routine HPV testing. The results showed a true negative HPV PCR invariably indicates the absence of precancerous cells in the cytology samples. However, 80.5% of single positive HPV-16 tests and 97.3% of single positive HPV-18 tests were associated with a negative or a largely self-reversible Pap cytology. Routine sensitive and reliable HPV type-specific or perhaps even variant-specific methods are needed to address the issues of persistence of HPV infection if a virology-based primary cervical screen is used to replace the Pap cytology screening paradigm. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessArticle Oral Human Papillomavirus (HPV) Infection among Unvaccinated High-Risk Young Adults
Cancers 2014, 6(3), 1691-1704; doi:10.3390/cancers6031691
Received: 20 June 2014 / Revised: 24 July 2014 / Accepted: 6 August 2014 / Published: 14 August 2014
Cited by 9 | PDF Full-text (918 KB) | HTML Full-text | XML Full-text
Abstract
Oral HPV infection, the cause of most oropharyngeal cancer in the U.S., is not well studied among high-risk young adults. Men (n = 340) and women (n = 270) aged 18–25 years attending Baltimore County STD clinics were recruited if they
[...] Read more.
Oral HPV infection, the cause of most oropharyngeal cancer in the U.S., is not well studied among high-risk young adults. Men (n = 340) and women (n = 270) aged 18–25 years attending Baltimore County STD clinics were recruited if they declined HPV vaccination. Each participant had a 30-second oral rinse and gargle sample tested for 37 types of HPV DNA, and a risk-factor survey. Factors associated with prevalent infection were explored using log binomial regression. Men had higher prevalence of any oral HPV (15.3% vs. 7.8%, p = 0.004) and vaccine-type oral HPV (i.e., HPV16/18/6/11: 5.0% vs. 1.1%, p = 0.007) infection than women. In multivariate analysis, male gender (aPR = 1.93, 95% CI = 1.10–3.39), number of recent oral sex partners (p-trend = 0.013) and having ever performed oral sex on a woman (aPR = 1.73, 95% CI = 1.06–2.82) were associated with increased oral HPV prevalence. Performing oral sex on a woman may confer higher risk of oral HPV acquisition than performing oral sex on a man. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessArticle An RNA Aptamer Targets the PDZ-Binding Motif of the HPV16 E6 Oncoprotein
Cancers 2014, 6(3), 1553-1569; doi:10.3390/cancers6031553
Received: 20 May 2014 / Revised: 23 June 2014 / Accepted: 3 July 2014 / Published: 24 July 2014
Cited by 5 | PDF Full-text (777 KB) | HTML Full-text | XML Full-text
Abstract
Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus which is the primary causative agent of cervical cancer. Cell transformation arises from deregulated expression of the E6 and E7 oncogenes. E6 has been shown to bind a number of cellular proteins, including
[...] Read more.
Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus which is the primary causative agent of cervical cancer. Cell transformation arises from deregulated expression of the E6 and E7 oncogenes. E6 has been shown to bind a number of cellular proteins, including p53 and proteins containing a PDZ domain. This study reports the first RNA aptamers to E6. These have been employed as molecular tools to further investigate E6-p53 and E6-PDZ interactions. This study is focussed on two aptamers (termed F2 and F4) which induced apoptosis in cells derived from an HPV16-transformed cervical carcinoma. The molecules were able to inhibit the interaction between E6 and PDZ1 from Magi1, with F2 being the most effective inhibitor. Neither of the aptamers inhibited E6-p53 interaction or p53 degradation. This study shows the specificity of this approach and highlights the potential benefits of the E6 aptamers as potential therapeutic or diagnostic agents in the future. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Figures

Review

Jump to: Research

Open AccessReview Human BK Polyomavirus—The Potential for Head and Neck Malignancy and Disease
Cancers 2015, 7(3), 1244-1270; doi:10.3390/cancers7030835
Received: 14 May 2015 / Revised: 25 June 2015 / Accepted: 25 June 2015 / Published: 8 July 2015
PDF Full-text (550 KB) | HTML Full-text | XML Full-text
Abstract
Members of the human Polyomaviridae family are ubiquitous and pathogenic among immune-compromised individuals. While only Merkel cell polyomavirus (MCPyV) has conclusively been linked to human cancer, all members of the polyomavirus (PyV) family encode the oncoprotein T antigen and may be potentially carcinogenic.
[...] Read more.
Members of the human Polyomaviridae family are ubiquitous and pathogenic among immune-compromised individuals. While only Merkel cell polyomavirus (MCPyV) has conclusively been linked to human cancer, all members of the polyomavirus (PyV) family encode the oncoprotein T antigen and may be potentially carcinogenic. Studies focusing on PyV pathogenesis in humans have become more abundant as the number of PyV family members and the list of associated diseases has expanded. BK polyomavirus (BKPyV) in particular has emerged as a new opportunistic pathogen among HIV positive individuals, carrying harmful implications. Increasing evidence links BKPyV to HIV-associated salivary gland disease (HIVSGD). HIVSGD is associated with elevated risk of lymphoma formation and its prevalence has increased among HIV/AIDS patients. Determining the relationship between BKPyV, disease and tumorigenesis among immunosuppressed individuals is necessary and will allow for expanding effective anti-viral treatment and prevention options in the future. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessReview Chromatinization of the KSHV Genome During the KSHV Life Cycle
Cancers 2015, 7(1), 112-142; doi:10.3390/cancers7010112
Received: 28 October 2014 / Accepted: 7 January 2015 / Published: 14 January 2015
Cited by 3 | PDF Full-text (1115 KB) | HTML Full-text | XML Full-text
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family and is the causative agent of various lymphoproliferative diseases in humans. KSHV, like other herpesviruses, establishes life-long latent infection with the expression of a limited number of viral genes. Expression of these genes
[...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family and is the causative agent of various lymphoproliferative diseases in humans. KSHV, like other herpesviruses, establishes life-long latent infection with the expression of a limited number of viral genes. Expression of these genes is tightly regulated by both the viral and cellular factors. Recent advancements in identifying the expression profiles of viral transcripts, using tilling arrays and next generation sequencing have identified additional coding and non-coding transcripts in the KSHV genome. Determining the functions of these transcripts will provide a better understanding of the mechanisms utilized by KSHV in altering cellular pathways involved in promoting cell growth and tumorigenesis. Replication of the viral genome is critical in maintaining the existing copies of the viral episomes during both latent and lytic phases of the viral life cycle. The replication of the viral episome is facilitated by viral components responsible for recruiting chromatin modifying enzymes and replication factors for altering the chromatin complexity and replication initiation functions, respectively. Importantly, chromatin modification of the viral genome plays a crucial role in determining whether the viral genome will persist as latent episome or undergo lytic reactivation. Additionally, chromatinization of the incoming virion DNA, which lacks chromatin structure, in the target cells during primary infection, helps in establishing latent infection. Here, we discuss the recent advancements on our understating of KSHV genome chromatinization and the consequences of chromatin modifications on viral life cycle. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessReview Epstein-Barr Virus in Gastric Carcinoma
Cancers 2014, 6(4), 2259-2274; doi:10.3390/cancers6042259
Received: 28 May 2014 / Revised: 27 September 2014 / Accepted: 28 October 2014 / Published: 7 November 2014
Cited by 12 | PDF Full-text (901 KB) | HTML Full-text | XML Full-text
Abstract
The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma, all tumor cells harbor the clonal EBV genome. Gastric carcinoma associated with EBV has distinct clinicopathological features, occurs predominately in men and in
[...] Read more.
The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma, all tumor cells harbor the clonal EBV genome. Gastric carcinoma associated with EBV has distinct clinicopathological features, occurs predominately in men and in younger-aged individuals, and presents a generally diffuse histological type. Most cases of EBV-associated gastric carcinoma exhibit a histology rich in lymphocyte infiltration. The immunological reactiveness in the host may represent a relatively preferable prognosis in EBV-positive cases. This fact highlights the important role of EBV in the development of EBV-associated gastric carcinoma. We have clearly proved direct infection of human gastric epithelialcells by EBV. The infection was achieved by using a recombinant EBV. Promotion of growth by EBV infection was observed in the cells. Considerable data suggest that EBV may directly contribute to the development of EBV-associated GC. This tumor-promoting effect seems to involve multiple mechanisms, because EBV affects several host proteins and pathways that normally promote apoptosis and regulate cell proliferation. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessReview Viral Carcinogenesis: Factors Inducing DNA Damage and Virus Integration
Cancers 2014, 6(4), 2155-2186; doi:10.3390/cancers6042155
Received: 31 July 2014 / Revised: 3 October 2014 / Accepted: 9 October 2014 / Published: 22 October 2014
Cited by 8 | PDF Full-text (571 KB) | HTML Full-text | XML Full-text
Abstract
Viruses are the causative agents of 10%–15% of human cancers worldwide. The most common outcome for virus-induced reprogramming is genomic instability, including accumulation of mutations, aberrations and DNA damage. Although each virus has its own specific mechanism for promoting carcinogenesis, the majority of
[...] Read more.
Viruses are the causative agents of 10%–15% of human cancers worldwide. The most common outcome for virus-induced reprogramming is genomic instability, including accumulation of mutations, aberrations and DNA damage. Although each virus has its own specific mechanism for promoting carcinogenesis, the majority of DNA oncogenic viruses encode oncogenes that transform infected cells, frequently by targeting p53 and pRB. In addition, integration of viral DNA into the human genome can also play an important role in promoting tumor development for several viruses, including HBV and HPV. Because viral integration requires the breakage of both the viral and the host DNA, the integration rate is believed to be linked to the levels of DNA damage. DNA damage can be caused by both endogenous and exogenous factors, including inflammation induced by either the virus itself or by co-infections with other agents, environmental agents and other factors. Typically, cancer develops years to decades following the initial infection. A better understanding of virus-mediated carcinogenesis, the networking of pathways involved in transformation and the relevant risk factors, particularly in those cases where tumorigenesis proceeds by way of virus integration, will help to suggest prophylactic and therapeutic strategies to reduce the risk of virus-mediated cancer. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessReview SUMO and KSHV Replication
Cancers 2014, 6(4), 1905-1924; doi:10.3390/cancers6041905
Received: 11 June 2014 / Revised: 9 September 2014 / Accepted: 10 September 2014 / Published: 29 September 2014
Cited by 4 | PDF Full-text (1019 KB) | HTML Full-text | XML Full-text
Abstract
Small Ubiquitin-related MOdifier (SUMO) modification was initially identified as a reversible post-translational modification that affects the regulation of diverse cellular processes, including signal transduction, protein trafficking, chromosome segregation, and DNA repair. Increasing evidence suggests that the SUMO system also plays an important role
[...] Read more.
Small Ubiquitin-related MOdifier (SUMO) modification was initially identified as a reversible post-translational modification that affects the regulation of diverse cellular processes, including signal transduction, protein trafficking, chromosome segregation, and DNA repair. Increasing evidence suggests that the SUMO system also plays an important role in regulating chromatin organization and transcription. It is thus not surprising that double-stranded DNA viruses, such as Kaposi’s sarcoma-associated herpesvirus (KSHV), have exploited SUMO modification as a means of modulating viral chromatin remodeling during the latent-lytic switch. In addition, SUMO regulation allows the disassembly and assembly of promyelocytic leukemia protein-nuclear bodies (PML-NBs), an intrinsic antiviral host defense, during the viral replication cycle. Overcoming PML-NB-mediated cellular intrinsic immunity is essential to allow the initial transcription and replication of the herpesvirus genome after de novo infection. As a consequence, KSHV has evolved a way as to produce multiple SUMO regulatory viral proteins to modulate the cellular SUMO environment in a dynamic way during its life cycle. Remarkably, KSHV encodes one gene product (K-bZIP) with SUMO-ligase activities and one gene product (K-Rta) that exhibits SUMO-targeting ubiquitin ligase (STUbL) activity. In addition, at least two viral products are sumoylated that have functional importance. Furthermore, sumoylation can be modulated by other viral gene products, such as the viral protein kinase Orf36. Interference with the sumoylation of specific viral targets represents a potential therapeutic strategy when treating KSHV, as well as other oncogenic herpesviruses. Here, we summarize the different ways KSHV exploits and manipulates the cellular SUMO system and explore the multi-faceted functions of SUMO during KSHV’s life cycle and pathogenesis. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessReview Human Papillomavirus Induced Transformation in Cervical and Head and Neck Cancers
Cancers 2014, 6(3), 1793-1820; doi:10.3390/cancers6031793
Received: 14 July 2014 / Revised: 13 August 2014 / Accepted: 25 August 2014 / Published: 15 September 2014
Cited by 12 | PDF Full-text (707 KB) | HTML Full-text | XML Full-text
Abstract
Human papillomavirus (HPV) is one of the most widely publicized and researched pathogenic DNA viruses. For decades, HPV research has focused on transforming viral activities in cervical cancer. During the past 15 years, however, HPV has also emerged as a major etiological agent
[...] Read more.
Human papillomavirus (HPV) is one of the most widely publicized and researched pathogenic DNA viruses. For decades, HPV research has focused on transforming viral activities in cervical cancer. During the past 15 years, however, HPV has also emerged as a major etiological agent in cancers of the head and neck, in particular squamous cell carcinoma. Even with significant strides achieved towards the screening and treatment of cervical cancer, and preventive vaccines, cervical cancer remains the leading cause of cancer-associated deaths for women in developing countries. Furthermore, routine screens are not available for those at risk of head and neck cancer. The current expectation is that HPV vaccination will prevent not only cervical, but also head and neck cancers. In order to determine if previous cervical cancer models for HPV infection and transformation are directly applicable to head and neck cancer, clinical and molecular disease aspects must be carefully compared. In this review, we briefly discuss the cervical and head and neck cancer literature to highlight clinical and genomic commonalities. Differences in prognosis, staging and treatment, as well as comparisons of mutational profiles, viral integration patterns, and alterations in gene expression will be addressed. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessReview Human Papillomavirus in Head and Neck Cancer
Cancers 2014, 6(3), 1705-1726; doi:10.3390/cancers6031705
Received: 30 May 2014 / Revised: 6 August 2014 / Accepted: 7 August 2014 / Published: 18 August 2014
Cited by 13 | PDF Full-text (723 KB) | HTML Full-text | XML Full-text
Abstract
Human papillomavirus (HPV) is currently considered to be a major etiologic factor, in addition to tobacco and alcohol, for oropharyngeal cancer (OPC) development. HPV positive OPCs are epidemiologically distinct from HPV negative ones, and are characterized by younger age at onset, male predominance,
[...] Read more.
Human papillomavirus (HPV) is currently considered to be a major etiologic factor, in addition to tobacco and alcohol, for oropharyngeal cancer (OPC) development. HPV positive OPCs are epidemiologically distinct from HPV negative ones, and are characterized by younger age at onset, male predominance, and strong association with sexual behaviors. HPV16 is the most prevalent types in oral cavity cancer (OCC), moreover the prevalence of beta, and gamma HPV types is higher than that of alpha HPV in oral cavity. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)
Open AccessReview Epstein-Barr Virus-Encoded RNAs: Key Molecules in Viral Pathogenesis
Cancers 2014, 6(3), 1615-1630; doi:10.3390/cancers6031615
Received: 20 June 2014 / Revised: 18 July 2014 / Accepted: 21 July 2014 / Published: 6 August 2014
Cited by 16 | PDF Full-text (470 KB) | HTML Full-text | XML Full-text
Abstract
The Epstein-Barr virus (EBV) is known as an oncogenic herpesvirus that has been implicated in the pathogenesis of various malignancies. EBV-encoded RNAs (EBERs) are non-coding RNAs expressed abundantly in latently EBV-infected cells. Herein, I summarize the current understanding of the functions of EBERs,
[...] Read more.
The Epstein-Barr virus (EBV) is known as an oncogenic herpesvirus that has been implicated in the pathogenesis of various malignancies. EBV-encoded RNAs (EBERs) are non-coding RNAs expressed abundantly in latently EBV-infected cells. Herein, I summarize the current understanding of the functions of EBERs, including the interactions with cellular factors through which EBERs contribute to EBV-mediated pathogenesis. Previous studies have demonstrated that EBERs are responsible for malignant phenotypes in lymphoid cells, and can induce several cytokines that can promote the growth of various EBV-infected cancer cells. EBERs were also found to bind retinoic acid-inducible gene I (RIG-I) and thus activate its downstream signaling. Furthermore, EBERs induce interleukin-10, an autocrine growth factor for Burkitt’s lymphoma cells, by activating RIG-I/interferon regulatory factor 3 pathway, suggesting that EBER-mediated innate immune signaling modulation contributes to EBV-mediated oncogenesis. Recently, EBV-infected cells were reported to secret EBERs, which were then recognized by toll-like receptor 3 (TLR3), leading to the induction of type I interferon and inflammatory cytokines, and subsequent immune activation. Furthermore, EBER1 was detected in the sera of patients with active EBV-infectious diseases, suggesting that EBER1-meidated TLR3 signaling activation could account for the pathogenesis of active EBV-infectious diseases. Full article
(This article belongs to the Special Issue DNA Viruses in Human Cancer)

Journal Contact

MDPI AG
Cancers Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
cancers@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to Cancers
Back to Top