Tumour Virus Research最新文献

Approximately 20 % of human cancers are associated with virus infection. DNA tumor viruses can induce tumor formation in host cells by disrupting the cell's DNA replication and repair mechanisms. Specifically, these viruses interfere with the host cell's DNA damage response (DDR), which is a complex network of signaling pathways that is essential for maintaining the integrity of the genome. DNA tumor viruses can disrupt these pathways by expressing oncoproteins that mimic or inhibit various DDR components, thereby promoting genomic instability and tumorigenesis. Recent studies have highlighted the molecular mechanisms by which DNA tumor viruses interact with DDR components, as well as the ways in which these interactions contribute to viral replication and tumorigenesis. Understanding the interplay between DNA tumor viruses and the DDR pathway is critical for developing effective strategies to prevent and treat virally associated cancers. In this review, we discuss the current state of knowledge regarding the mechanisms by which human papillomavirus (HPV), merkel cell polyomavirus (MCPyV), Kaposi's sarcoma-associated herpesvirus (KSHV), and Epstein-Barr virus (EBV) interfere with DDR pathways to facilitate their respective life cycles, and the consequences of such interference on genomic stability and cancer development.

HBV infection profoundly escalates hepatocellular carcinoma (HCC) susceptibility, responsible for a majority of HCC cases. HBV-driven immune-mediated hepatocyte impairment significantly fuels HCC progression. Regrettably, inconspicuous early HCC symptoms often culminate in belated diagnoses. Nevertheless, surgically treated early-stage HCC patients relish augmented five-year survival rates. In contrast, advanced HCC exhibits feeble responses to conventional interventions like radiotherapy, chemotherapy, and surgery, leading to diminished survival rates. This investigation endeavors to unearth diagnostic hallmark genes for HBV-HCC leveraging a bioinformatics framework, thus refining early HBV-HCC detection. Candidate genes were sieved via differential analysis and Weighted Gene Co-Expression Network Analysis (WGCNA). Employing three distinct machine learning algorithms unearthed three feature genes (HHIP, CXCL14, and CDHR2). Melding these genes yielded an innovative Artificial Neural Network (ANN) diagnostic blueprint, portending to alleviate patient encumbrance and elevate life quality. Immunoassay scrutiny unveiled accentuated immune damage in HBV-HCC patients relative to solitary HCC. Through consensus clustering, HBV-HCC was stratified into two subtypes (C1 and C2), the latter potentially indicating milder immune impairment. The diagnostic model grounded in these feature genes showcased robust and transferrable prognostic potentialities, introducing a novel outlook for early HBV-HCC diagnosis. This exhaustive immunological odyssey stands poised to expedite immunotherapeutic curatives' emergence for HBV-HCC.

Several studies have described functional regulation of high-risk human papillomaviruses (HPVs), E6 and E7 oncoproteins via posttranslational modifications (PTMs). However, how these PTMs modulate the activity of E6 and E7, particularly in their targeting of cellular proteins, is not completely understood. In this study, we show that HPV16 E7 can be phosphorylated by casein kinase I (CKI) and glycogen synthase kinase 3 (GSK3). This principal phosphorylation occurs at threonine residues 5 and 7 with a more minor role for residues 19–20 in the N-terminal region of 16 E7. Intriguingly, whilst mutational analyses suggest that residues 5 and 7 may be dispensable for the transformation of primary baby rat kidney cells by E7, intact residues 19 and 20 are required. Furthermore, negative charges at these residues (TT19-20DD) enhance the pRb-E7 interaction and cells display increased proliferation and invasion capacities. Using a proteomic approach with a phosphorylated peptide spanning the TT19-20 region of HPV16 E7, we have identified a panel of new, phospho-specific E7 interacting partners. These results shed new light on the complexity of N-terminal phosphorylation of E7 and how this can contribute towards expanding the repertoire of E7 targeted pathways.

Problem

Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18.

Methods

We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues.

Results

rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03–1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18–7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (p_ANOVA = 0.0009), with the risk allele lowering mRNA levels.

Conclusions

We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies.

The incorporation of HPV DNA testing into cervical screening programs has shown that many HPV-positive women are cytologically normal, with HPV-positivity fluctuating throughout life. Such results suggest that papillomaviruses may persist in a latent state after disease clearance, with sporadic recurrence. It appears that virus latency represents a narrow slot in a wider spectrum of subclinical and possibly productive infections. Clinical studies, and animal model infection studies, suggested a key role for host immune surveillance in maintaining such asymptomatic infections, and although infections may also be cleared, most studies have used the term ‘clearance’ to describe a situation where the presence of HPV DNA falls below the clinical detection level. Given our knowledge of papillomavirus immune evasion strategies and the restricted pattern of viral gene expression required for ‘basal cell’ persistence, the term ‘apparent clearance’ and ‘subclinical persistence’ of infection may better summarise our understanding. Subclinical infection also encompasses the lag phase, which occurs between infection and lesion development. This is dependent on infection titre, with multifocal infections developing more rapidly to disease. These concepts can usefully influence patient management where HPV-positivity occurs sometime after the onset of sexual activity, and where vertical transmission is suspected despite a lag period.

The International Papillomavirus Conference was held in Washington DC in April 2023 and encompassed wide ranging basic, clinical and public health research relating to animal and human papillomaviruses. This editorial is a personal reflection, it does not attempt to be comprehensive and reports on some key aspects centred on the prospects for immune interventions in prevention and treatment of HPV infections and early precancers with a focus on cervical neoplasia. There is optimism for the future impact of immunotherapy in treating early HPV associated disease. This will depend on developing an appropriate design of vaccines and delivery vehicles which then need to be properly tested in clinical trials that are able to measure a useful clinical endpoint. Thereafter vaccines (prophylactic or therapeutic) still need global access and sufficient uptake to deliver impact and a key and necessary driver is education.

Merkel cell polyomavirus (MCV) and high-risk human papillomavirus (HPV) are human tumor viruses that cause Merkel cell carcinoma (MCC) and oropharyngeal squamous cell carcinoma (OSCC), respectively. HPV E7 and MCV large T (LT) oncoproteins target the retinoblastoma tumor suppressor protein (pRb) through the conserved LxCxE motif. We identified enhancer of zeste homolog 2 (EZH2) as a common host oncoprotein activated by both viral oncoproteins through the pRb binding motif. EZH2 is a catalytic subunit of the polycomb 2 (PRC2) complex that trimethylates histone H3 at lysine 27 (H3K27me3). In MCC tissues EZH2 was highly expressed, irrespective of MCV status. Loss-of-function studies revealed that viral HPV E6/E7 and T antigen expression are required for Ezh2 mRNA expression and that EZH2 is essential for HPV(+)OSCC and MCV(+)MCC cell growth. Furthermore, EZH2 protein degraders reduced cell viability efficiently and rapidly in HPV(+)OSCC and MCV(+)MCC cells, whereas EZH2 histone methyltransferase inhibitors did not affect cell proliferation or viability within the same treatment period. These results suggest that a methyltransferase-independent function of EZH2 contributes to tumorigenesis downstream of two viral oncoproteins, and that direct targeting of EZH2 protein expression could be a promising strategy for the inhibition of tumor growth in HPV(+)OSCC and MCV(+)MCC patients.

Human papillomavirus (HPV) E6 and E7 oncogene expression is essential for cervical carcinogenesis. Evidence exists that E6/E7 variants may have different transforming activities while the risk of HPV-16 variants (A/D) differs by race/ethnicity. We determined the type-specific diversity of HPV infection in women with high grade cervical disease or cervical cancer in Ghana and investigated naturally occurring E6/E7 DNA variants in this population. HPV genotyping was carried out on 207 cervical swab samples collected from women referred to a gynaecology clinic at two teaching hospitals in Ghana. HPV-16, HPV-18 and HPV-45 were detected in 41.9%, 23.3% and 16.3% of cases respectively. HPV-16 E6/E7 DNA sequencing was performed in 36 samples. Thirty samples contained E6/E7 variants of the HPV-16-B/C lineage. 21/36 samples were of the HPV-16C1 sublineage variant and all contained the E7 A647G(N29S) single nucleotide polymorphism (SNP). This study reveals the diversity of E6/E7 DNA and the dominance of HPV16 B/C variants in cervicovaginal HPV infection in Ghana. Type-specific HPV diversity analysis indicates that most Ghanaian cervical disease cases are vaccine preventable. The study provides an important baseline from which for the impact of vaccine and antivirals on clinically relevant HPV infection and associated disease can be measured.

Australia's cervical screening program transitioned from cytology to HPV-testing with genotyping for HPV16/18 in Dec’2017. We investigated whether program data could be used to monitor HPV vaccination program impact (commenced in 2007) on HPV16/18 prevalence and compared estimates with pre-vaccination benchmark prevalence. Pre-vaccination samples (2005–2008) (n = 1933; WHINURS), from 25 to 64-year-old women had been previously analysed with Linear Array (LA). Post-vaccination samples (2013-2014) (n = 2989; Compass pilot), from 25 to 64-year-old women, were analysed by cobas 4800 (cobas), and by LA for historical comparability. Age standardised pre-vaccination HPV16/18 prevalence was 4.85% (95%CI:3.81–5.89) by LA; post-vaccination estimates were 1.67% (95%CI:1.21–2.13%) by LA, 1.49% (95%CI:1.05–1.93%) by cobas, and 1.63% (95%CI:1.17–2.08%) for cobas and LA testing of non-16/18 cobas positives (cobas/LA). Age-standardised pre-vaccination oncogenic HPV prevalence was 15.70% (95%CI:13.79–17.60%) by LA; post-vaccination estimates were 9.06% (95%CI:8.02–10.09%) by LA, 8.47% (95%CI:7.47–9.47%) by cobas and cobas/LA. Standardised rate ratios between post-vs. pre-vaccination rates were significantly different for HPV16/18, non-16/18 HPV and oncogenic HPV: 0.34 (95%CI:0.23–0.50), 0.68 (95%CI:0.55–0.84) and 0.58 (95%CI:0.48–0.69), respectively. Additional strategies (LA for all cobas positives; combined cobas and LA results on all samples) had similar results. If a single method is applied consistently, it will provide important data on relative changes in HPV prevalence following vaccination.

Previous studies have shown that the high-risk HPV E6 oncoprotein PDZ binding motifs (PBMs) can interact with PDZ proteins or members of the 14-3-3 family, depending upon the E6 phosphorylation status. However, different HPV E6 oncoproteins are subjected to phosphorylation by different cellular kinases. We have therefore been interested in determining whether we can dissect E6's PDZ and 14-3-3 interactions at the molecular level. Using HPV-18 E6, we have found that its Chk1 phosphorylation requires residues both upstream and downstream of the phospho-acceptor site, in addition to the Chk1 consensus recognition motif. Furthermore, we demonstrate that different high-risk HPV E6 types are differentially phosphorylated by Chk1 kinases, potentially due to the differences in their carboxy-terminal residues, as they are critical for kinase recognition. Moreover, differences in the E6 phosphorylation levels of different HR HPV types directly link to their ability to interact with different 14-3-3 isoforms, based on their phospho-status. Interestingly, 14-3-3 recognition appears to be less dependent upon the precise sequence constraints of the E6 carboxy terminal region, whilst minor amino acid variations have a major impact upon PDZ recognition. These results demonstrate that changes in E6 phospho-status during the life cycle or during malignant progression will modulate E6 interactions and, potentially, inversely regulate the levels of PDZ and 14-3-3 proteins.