Pub Date : 2025-11-01DOI: 10.1016/j.tvr.2025.200329
Ashley N. Della Fera, Dan Chen, Alison A. McBride
The circular, double-stranded DNA genomes of Human papillomaviruses (HPV) exist in a nucleosomal state throughout the infectious cycle and rely on host histone epigenetic modifications and chromatin assembly processes to promote various phases of the viral life cycle. Here, we show that the histone H3.3 chaperone HIRA and its associated complex members are recruited to HPV replication factories during the late phase of the HPV life cycle. HIRA is also recruited to HPV replication factories generated by amplification of a replicon with a minimal origin and expression of the viral replication proteins E1 and E2, demonstrating that the E1 and E2 proteins are sufficient for HIRA recruitment. Downregulation of HIRA expression reduces HPV31 DNA amplification and viral transcription in differentiated keratinocytes. Histone H3.3 that is highly phosphorylated on serine residue 31 is also enriched at sites of HPV replication and this modification links the DNA damage response to chromatin that supports rapid gene activation. We propose that deposition of histone H3.3 generates viral minichromosomes which are highly primed to support the late stages of the HPV life cycle.
{"title":"Chromatin assembly by the histone chaperone HIRA facilitates Human Papillomavirus replication","authors":"Ashley N. Della Fera, Dan Chen, Alison A. McBride","doi":"10.1016/j.tvr.2025.200329","DOIUrl":"10.1016/j.tvr.2025.200329","url":null,"abstract":"<div><div>The circular, double-stranded DNA genomes of Human papillomaviruses (HPV) exist in a nucleosomal state throughout the infectious cycle and rely on host histone epigenetic modifications and chromatin assembly processes to promote various phases of the viral life cycle. Here, we show that the histone H3.3 chaperone HIRA and its associated complex members are recruited to HPV replication factories during the late phase of the HPV life cycle. HIRA is also recruited to HPV replication factories generated by amplification of a replicon with a minimal origin and expression of the viral replication proteins E1 and E2, demonstrating that the E1 and E2 proteins are sufficient for HIRA recruitment. Downregulation of HIRA expression reduces HPV31 DNA amplification and viral transcription in differentiated keratinocytes. Histone H3.3 that is highly phosphorylated on serine residue 31 is also enriched at sites of HPV replication and this modification links the <span>DNA</span> damage response to chromatin that supports rapid gene activation. We propose that deposition of histone H3.3 generates viral minichromosomes which are highly primed to support the late stages of the HPV life cycle.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"20 ","pages":"Article 200329"},"PeriodicalIF":8.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145439955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-22DOI: 10.1016/j.tvr.2025.200328
Tina M. Rehm, Christina Parpoulas, Elke Straub, Thomas Iftner, Frank Stubenrauch
Epidermodysplasia verruciformis (EV) is an autosomal recessive disorder characterized by an extraordinary susceptibility to infections with human papillomaviruses (HPV), mainly from the genus beta. EV patients carry biallelic loss-of-function mutations in TMC6 encoding Transmembrane channel-like protein 6 or EV protein 1 (EVER1), TMC8 encoding Transmembrane channel-like protein 8 or EV protein 2 (EVER2), or CIB1 encoding Calcium and integrin-binding protein 1. TMC6, TMC8 and CIB1 form a protein complex in the endoplasmic reticulum which has been hypothesized to act as a restriction factor for beta-HPV in keratinocytes. SiRNA-mediated knock-down of CIB1, TMC6, or TMC8 greatly reduces transcript and protein levels, but does not activate beta-HPV8 gene expression in normal keratinocytes. TMC6 and TMC8 transcript levels are much lower in normal and HPV-positive human keratinocytes than in CD4+ T-cells suggesting that the levels are too low for anti-viral activity. However, neither the activation of DNA sensing pathways by HPV genomes, supernatants from activated immune cells, nor activation of pathways important for the viral life cycle such as the DNA damage response or keratinocyte differentiation induce high levels of TMC6 or TMC8 in normal keratinocytes. This is consistent with findings that TMC6 and TMC8 do not restrict Mus musculus PV1 expression in keratinocytes. Taken together, we find no evidence for restriction factor activity of EV susceptibility genes for beta-HPV8 or conditions to induce high levels of TMC6 and TMC8 in keratinocytes. Thus, it is plausible that the EV phenotype in humans may be associated with an immune deficiency involving immune cells.
{"title":"No evidence for restriction of Beta-HPV8 gene expression by epidermodysplasia verruciformis susceptibility genes CIB1, TMC6, or TMC8 in keratinocytes","authors":"Tina M. Rehm, Christina Parpoulas, Elke Straub, Thomas Iftner, Frank Stubenrauch","doi":"10.1016/j.tvr.2025.200328","DOIUrl":"10.1016/j.tvr.2025.200328","url":null,"abstract":"<div><div><em>Epidermodysplasia verruciformis</em> (EV) is an autosomal recessive disorder characterized by an extraordinary susceptibility to infections with human papillomaviruses (HPV), mainly from the genus beta. EV patients carry biallelic loss-of-function mutations in <em>TMC6</em> encoding Transmembrane channel-like protein 6 or EV protein 1 (EVER1), <em>TMC8</em> encoding Transmembrane channel-like protein 8 or EV protein 2 (EVER2), or <em>CIB1</em> encoding Calcium and integrin-binding protein 1. TMC6, TMC8 and CIB1 form a protein complex in the endoplasmic reticulum which has been hypothesized to act as a restriction factor for beta-HPV in keratinocytes. SiRNA-mediated knock-down of CIB1, TMC6, or TMC8 greatly reduces transcript and protein levels, but does not activate beta-HPV8 gene expression in normal keratinocytes. <em>TMC6</em> and <em>TMC8</em> transcript levels are much lower in normal and HPV-positive human keratinocytes than in CD4<sup>+</sup> T-cells suggesting that the levels are too low for anti-viral activity. However, neither the activation of DNA sensing pathways by HPV genomes, supernatants from activated immune cells, nor activation of pathways important for the viral life cycle such as the DNA damage response or keratinocyte differentiation induce high levels of TMC6 or TMC8 in normal keratinocytes. This is consistent with findings that TMC6 and TMC8 do not restrict Mus musculus PV1 expression in keratinocytes. Taken together, we find no evidence for restriction factor activity of EV susceptibility genes for beta-HPV8 or conditions to induce high levels of TMC6 and TMC8 in keratinocytes. Thus, it is plausible that the EV phenotype in humans may be associated with an immune deficiency involving immune cells.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"20 ","pages":"Article 200328"},"PeriodicalIF":8.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145369359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-17DOI: 10.1016/j.tvr.2025.200325
Preetiparna Parida , Nivedita Mukherjee , Agastya Singh , Shirley Lewis , Krishna Sharan , Sandeep Mallya , Ashima Singh , Surya Sarathi Das , Mahadev Rao , Daniel S. Higginson , Radhakrishnan Sabarinathan , Rama Rao Damerla
Human papillomaviral (HPV) integrations into host human genome, a frequently observed event in HPV associated cervical cancer, are currently mapped through expensive Whole Genome sequencing (WGS) or RNA sequencing (RNA-seq) methodologies. This study aims to develop a targeted sequencing assay to determine HPV integrations in cervical tumors without the need for WGS or RNA-seq. We employed a library preparation strategy using tiled single primers that bind to HPV genome as a template and possibly extend HPV sequences into adjacent host human genomic sequences resulting in HPV and human chimeric sequences. Using this strategy, we sequenced known HPV integrations in HPV18 positive HeLa and HPV16 positive SiHa cell lines. We further used this method to detect HPV integration sites in four HPV-positive cervical cancer patients and confirmed these integration breakpoints by WGS and Sanger sequencing. Functional impact of HPV integrations was explored through differentially expressed genes within or near topologically associating domain (TAD) boundaries, possibly disrupted by respective integration events in these patients. We found ZFP36L1, CPA3, CPB1 and CXCL8 as some of the differentially expressed genes within disrupted TADs, which are known cancer associated genes. Our approach also reduced the cost of HPV integration detection by 90 % compared to WGS while also minimizing sequencing data volume. We believe that this method captures HPV integrations at significantly reduced costs and lesser sequencing data volume leading to better understanding of disease progression and monitoring cancer treatment.
{"title":"Precise identification of viral–host integration events in HPV-positive cervical cancers by targeted long-read sequencing","authors":"Preetiparna Parida , Nivedita Mukherjee , Agastya Singh , Shirley Lewis , Krishna Sharan , Sandeep Mallya , Ashima Singh , Surya Sarathi Das , Mahadev Rao , Daniel S. Higginson , Radhakrishnan Sabarinathan , Rama Rao Damerla","doi":"10.1016/j.tvr.2025.200325","DOIUrl":"10.1016/j.tvr.2025.200325","url":null,"abstract":"<div><div>Human papillomaviral (HPV) integrations into host human genome, a frequently observed event in HPV associated cervical cancer, are currently mapped through expensive Whole Genome sequencing (WGS) or RNA sequencing (RNA-seq) methodologies. This study aims to develop a targeted sequencing assay to determine HPV integrations in cervical tumors without the need for WGS or RNA-seq. We employed a library preparation strategy using tiled single primers that bind to HPV genome as a template and possibly extend HPV sequences into adjacent host human genomic sequences resulting in HPV and human chimeric sequences. Using this strategy, we sequenced known HPV integrations in HPV18 positive HeLa and HPV16 positive SiHa cell lines. We further used this method to detect HPV integration sites in four HPV-positive cervical cancer patients and confirmed these integration breakpoints by WGS and Sanger sequencing. Functional impact of HPV integrations was explored through differentially expressed genes within or near topologically associating domain (TAD) boundaries, possibly disrupted by respective integration events in these patients. We found <em>ZFP36L1, CPA3, CPB1</em> and <em>CXCL8</em> as some of the differentially expressed genes within disrupted TADs, which are known cancer associated genes. Our approach also reduced the cost of HPV integration detection by 90 % compared to WGS while also minimizing sequencing data volume. We believe that this method captures HPV integrations at significantly reduced costs and lesser sequencing data volume leading to better understanding of disease progression and monitoring cancer treatment.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"20 ","pages":"Article 200325"},"PeriodicalIF":4.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-16DOI: 10.1016/j.tvr.2025.200324
João P. Cavasin , Min-Chun Chen , Harout Ajoyan , Melanie J. Dobromylskyj , Wei-Hsiang Huang , Mason Jager , Kate Van Brussel , Rebecca Rockett , Omid Nekouei , Penny Watson , Jason Bestwick , Yan Ru Choi , Jonathan A. Lidbury , John M. Cullen , Edward Holmes , Jörg M. Steiner , Thomas Tu , Julia A. Beatty
Hepatitis B virus (HBV) is the major cause of hepatocellular carcinoma (HCC) in humans. Domestic cat hepatitis B virus (DCHBV) naturally infects cats worldwide, but the oncogenic potential of this hepadnavirus is unclear. We investigated whether DCHBV contributes to feline HCC. Feline liver biopsies diagnosed with HCC (cases) and lymphocytic cholangitis (controls) were tested for DCHBV DNA by PCR. DCHBV-positive HCCs were further characterised by in situ hybridisation (ISH), whole-genome sequencing (WGS) and phylogenetic analysis. Targeted capture sequencing was used to identify and map viral DNA integrations. DCHBV DNA was detected in 17/71 (23.9 %) HCCs versus 0/88 controls (P < 0.001). ISH confirmed hepatocyte-specific viral localization. Phylogenetic analysis placed six viruses in genotype A, and a seventh divergent virus in genotype B virus. Virus-host chimeric sequences, consistent with integration sites, were identified in 11/16 PCR-positive HCCs. Eight of the 11 integration sites were independently confirmed with WGS. Viral termini in integrated DCHBV sequences corresponded to double-stranded linear DNA, the substrate for HBV integration. Five unique DCHBV integrations fell within, or were adjacent to, the promoter of the feline homologue of proto-oncogene CCNE1, a recurrent target for HBV integration in human HCC. Our findings reveal a compelling association between DCHBV detection and HCC in cats. Critically, virus integration in DCHBV-associated HCC is described for the first time, supporting that, like HBV, DCHBV can promote hepatocarcinogenesis by insertional mutagenesis. Clarification of fundamental DCHBV virology in vitro, and the consequences of natural infection could advance disease-prevention strategies for feline and human patients.
{"title":"Recurrent integration of domestic cat hepatitis B virus DNA near feline CCNE1 supports an oncogenic role in hepatocellular carcinoma in cats","authors":"João P. Cavasin , Min-Chun Chen , Harout Ajoyan , Melanie J. Dobromylskyj , Wei-Hsiang Huang , Mason Jager , Kate Van Brussel , Rebecca Rockett , Omid Nekouei , Penny Watson , Jason Bestwick , Yan Ru Choi , Jonathan A. Lidbury , John M. Cullen , Edward Holmes , Jörg M. Steiner , Thomas Tu , Julia A. Beatty","doi":"10.1016/j.tvr.2025.200324","DOIUrl":"10.1016/j.tvr.2025.200324","url":null,"abstract":"<div><div>Hepatitis B virus (HBV) is the major cause of hepatocellular carcinoma (HCC) in humans. Domestic cat hepatitis B virus (DCHBV) naturally infects cats worldwide, but the oncogenic potential of this hepadnavirus is unclear. We investigated whether DCHBV contributes to feline HCC. Feline liver biopsies diagnosed with HCC (cases) and lymphocytic cholangitis (controls) were tested for DCHBV DNA by PCR. DCHBV-positive HCCs were further characterised by <em>in situ</em> hybridisation (ISH), whole-genome sequencing (WGS) and phylogenetic analysis. Targeted capture sequencing was used to identify and map viral DNA integrations. DCHBV DNA was detected in 17/71 (23.9 %) HCCs versus 0/88 controls (P < 0.001). ISH confirmed hepatocyte-specific viral localization. Phylogenetic analysis placed six viruses in genotype A, and a seventh divergent virus in genotype B virus. Virus-host chimeric sequences, consistent with integration sites, were identified in 11/16 PCR-positive HCCs. Eight of the 11 integration sites were independently confirmed with WGS. Viral termini in integrated DCHBV sequences corresponded to double-stranded linear DNA, the substrate for HBV integration. Five unique DCHBV integrations fell within, or were adjacent to, the promoter of the feline homologue of proto-oncogene <em>CCNE1</em>, a recurrent target for HBV integration in human HCC. Our findings reveal a compelling association between DCHBV detection and HCC in cats. Critically, virus integration in DCHBV-associated HCC is described for the first time, supporting that, like HBV, DCHBV can promote hepatocarcinogenesis by insertional mutagenesis. Clarification of fundamental DCHBV virology <em>in vitro,</em> and the consequences of natural infection could advance disease-prevention strategies for feline and human patients.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"20 ","pages":"Article 200324"},"PeriodicalIF":8.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-09DOI: 10.1016/j.tvr.2025.200323
Marije Adriana Strikwerda , Sabrina Anouck Weerstand , George Louis Burchell , Jacqueline Maria Tromp , Constantijne Helene Mom , Tanja Denise de Gruijl
Background
Cervical cancer is the fourth most common malignancy in women worldwide and generally driven by persistent infection with high-risk human papillomavirus. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the two most common histological subtypes, with a relative increase in adenocarcinomas in the last decades. The immunological differences between cervical squamous cell carcinoma and adenocarcinoma remain largely unexplored. Understanding these distinctions is crucial for developing tailored therapies that can improve treatment outcomes for patients with cervical cancer. This systematic review provides an overview of the immunological features of squamous cell carcinoma and adenocarcinoma of the uterine cervix.
Methods
A systematic search was performed in PubMed, Embase.com, Web of Science, and Cochrane Library. All articles addressing immunological features of squamous cell carcinoma and adenocarcinoma of the uterine cervix were reviewed and included based on predefined inclusion and exclusion criteria.
Results
In total, 3207 articles were screened, of which 43 were included. Studies show that cervical squamous cell carcinomas are characterised by a more inflamed tumour microenvironment, but also contain more regulatory T cells and immune checkpoints. In contrast, adenocarcinomas are characterised by lower immune cell infiltration, contributing to its poorer prognosis and more limited response to treatment.
Conclusion
The observed differences emphasize the need for further research into subtype-specific differences and distinct therapeutic strategies. For squamous cell carcinomas, future research should focus on combinatorial immune checkpoint blockade, including regulatory T cell-depleting strategies. For adenocarcinomas, oncolytic virotherapy, therapeutic vaccination, and oncogenic signalling interference should be explored.
宫颈癌是世界范围内女性第四大常见恶性肿瘤，通常由高危人乳头瘤病毒持续感染引起。鳞状细胞癌（SCC）和腺癌（AC）是两种最常见的组织学亚型，在过去的几十年里腺癌的发病率相对增加。宫颈鳞状细胞癌和腺癌之间的免疫学差异在很大程度上仍未被研究。了解这些区别对于开发量身定制的治疗方法至关重要，可以改善宫颈癌患者的治疗效果。本文系统综述了宫颈鳞状细胞癌和腺癌的免疫学特征。方法系统检索PubMed、Embase.com、Web of Science、Cochrane Library。所有涉及宫颈鳞状细胞癌和腺癌的免疫学特征的文章都进行了审查，并根据预先确定的纳入和排除标准纳入。结果共筛选文献3207篇，纳入文献43篇。研究表明，宫颈鳞状细胞癌的特点是肿瘤微环境更炎症，但也含有更多的调节性T细胞和免疫检查点。相比之下，腺癌的特点是免疫细胞浸润较低，导致其预后较差，对治疗的反应较有限。结论观察到的差异强调需要进一步研究亚型特异性差异和明确的治疗策略。对于鳞状细胞癌，未来的研究应侧重于组合免疫检查点阻断，包括调节性T细胞消耗策略。对于腺癌，应探讨溶瘤病毒治疗、治疗性疫苗接种和致癌信号干扰。
{"title":"The immunological heterogeneity of squamous cell carcinoma and adenocarcinoma of the uterine cervix: a systematic review","authors":"Marije Adriana Strikwerda , Sabrina Anouck Weerstand , George Louis Burchell , Jacqueline Maria Tromp , Constantijne Helene Mom , Tanja Denise de Gruijl","doi":"10.1016/j.tvr.2025.200323","DOIUrl":"10.1016/j.tvr.2025.200323","url":null,"abstract":"<div><h3>Background</h3><div>Cervical cancer is the fourth most common malignancy in women worldwide and generally driven by persistent infection with high-risk human papillomavirus. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the two most common histological subtypes, with a relative increase in adenocarcinomas in the last decades. The immunological differences between cervical squamous cell carcinoma and adenocarcinoma remain largely unexplored. Understanding these distinctions is crucial for developing tailored therapies that can improve treatment outcomes for patients with cervical cancer. This systematic review provides an overview of the immunological features of squamous cell carcinoma and adenocarcinoma of the uterine cervix.</div></div><div><h3>Methods</h3><div>A systematic search was performed in PubMed, Embase.com, Web of Science, and Cochrane Library. All articles addressing immunological features of squamous cell carcinoma and adenocarcinoma of the uterine cervix were reviewed and included based on predefined inclusion and exclusion criteria.</div></div><div><h3>Results</h3><div>In total, 3207 articles were screened, of which 43 were included. Studies show that cervical squamous cell carcinomas are characterised by a more inflamed tumour microenvironment, but also contain more regulatory T cells and immune checkpoints. In contrast, adenocarcinomas are characterised by lower immune cell infiltration, contributing to its poorer prognosis and more limited response to treatment.</div></div><div><h3>Conclusion</h3><div>The observed differences emphasize the need for further research into subtype-specific differences and distinct therapeutic strategies. For squamous cell carcinomas, future research should focus on combinatorial immune checkpoint blockade, including regulatory T cell-depleting strategies. For adenocarcinomas, oncolytic virotherapy, therapeutic vaccination, and oncogenic signalling interference should be explored.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"20 ","pages":"Article 200323"},"PeriodicalIF":4.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-24DOI: 10.1016/j.tvr.2025.200322
Lanni Wang , Ruini Li , Haitao Ren , Chaoyi Jiang , Ye Shi , Bing Wang , Wenyu Jin , Jiaxue Wang , Linhua Lan , Feng Xu , Guangxin Xiang , Xiaoqun Zheng
Human cytomegalovirus (HCMV) infection and its association with tumorigenesis and tumor progression have garnered increasing attention. Previous research results have indicated that the detection rate of HCMV UL82 is higher in colorectal cancer (CRC) tissues and is correlated with poor prognosis in patients, yet the underlying mechanisms remain unclear. In this study, a cell model transfected with UL82 was established. Through in vitro and in vivo experiments, it was found that UL82 promoted the proliferation of CRC cells. Transcriptomic and metabolomic analyses revealed that UL82 could influence CRC glucose metabolism and cell proliferation by upregulating the key TCA cycle enzyme OGDH. Additionally, UL82 also affected CRC cell proliferation by upregulating the expression of ANGPT2, and silencing ANGPT2 resulted in a reduction in OGDH protein levels. Finally, through the investigation of the ubiquitin-mediated degradation pathway of OGDH, it was demonstrated that ANGPT2 inhibited the protein degradation of OGDH via deubiquitination, thereby maintaining its stability. In summary, UL82 promotes CRC cell proliferation by upregulating ANGPT2, which inhibits the ubiquitin-mediated degradation of OGDH, suggesting that targeting the UL82/ANGPT2/OGDH axis may offer a potential clinical strategy for the diagnosis of CRC.
{"title":"Human cytomegalovirus UL82 promotes colorectal cancer cell proliferation through inhibiting the ubiquitination of OGDH via ANGPT2","authors":"Lanni Wang , Ruini Li , Haitao Ren , Chaoyi Jiang , Ye Shi , Bing Wang , Wenyu Jin , Jiaxue Wang , Linhua Lan , Feng Xu , Guangxin Xiang , Xiaoqun Zheng","doi":"10.1016/j.tvr.2025.200322","DOIUrl":"10.1016/j.tvr.2025.200322","url":null,"abstract":"<div><div>Human cytomegalovirus (HCMV) infection and its association with tumorigenesis and tumor progression have garnered increasing attention. Previous research results have indicated that the detection rate of HCMV <em>UL82</em> is higher in colorectal cancer (CRC) tissues and is correlated with poor prognosis in patients, yet the underlying mechanisms remain unclear. In this study, a cell model transfected with UL82 was established. Through <em>in vitro</em> and <em>in vivo</em> experiments, it was found that UL82 promoted the proliferation of CRC cells. Transcriptomic and metabolomic analyses revealed that UL82 could influence CRC glucose metabolism and cell proliferation by upregulating the key TCA cycle enzyme OGDH. Additionally, UL82 also affected CRC cell proliferation by upregulating the expression of ANGPT2, and silencing ANGPT2 resulted in a reduction in OGDH protein levels. Finally, through the investigation of the ubiquitin-mediated degradation pathway of OGDH, it was demonstrated that ANGPT2 inhibited the protein degradation of OGDH via deubiquitination, thereby maintaining its stability. In summary, UL82 promotes CRC cell proliferation by upregulating ANGPT2, which inhibits the ubiquitin-mediated degradation of OGDH, suggesting that targeting the UL82/ANGPT2/OGDH axis may offer a potential clinical strategy for the diagnosis of CRC.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"20 ","pages":"Article 200322"},"PeriodicalIF":4.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Evaluating novel human papillomavirus (HPV) tests in well-designed, population-based screening studies is essential for ensuring the benefits of cervical cancer screening.
Methods
8638 women aged over 25 years from China underwent HPV screening using a PCR-based full genotyping HPV assay (SureX HPV), alongside hybrid-capture HPV tests (DH2/careHPV) and cytology. Any abnormal results triggered colposcopy and biopsy if indicated. Screening performance was evaluated for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+.
Results
The high-risk HPV (hrHPV) positive rate by SureX HPV was significantly higher than by careHPV (11.0 % vs. 8.2 %, P <0.01) but similar to DH2 HPV (12.0 % vs. 11.5 %, P =0.34). The overall agreement rates between SureX HPV and careHPV/DH2 HPV were 93.5 % (Kappa=0.63) and 94.0 % (Kappa=0.71). For CIN2+ detection, SureX HPV showed not-significantly higher sensitivity than careHPV (91.2 % vs 82.5 %, P =0.18) but lower specificity (91.2 % vs. 93.1 %, P <0.01). Compared to DH2, SureX HPV demonstrated comparable sensitivity (95.7 % for both, P =1.0) and specificity (89.5 % vs. 90.2 %, P =0.21). Similar patterns were observed for CIN3+ detection. The area under the receiver operating characteristic curve (AUC) for the SureX HPV was similar to hybrid-capture HPV tests (P >0.05 for both) and significantly higher than the cytology (ASC-US+) test for CIN2+/CIN3+ detection (P <0.05 for both).
Conclusions
The PCR-based SureX HPV test demonstrated good concordance with well-validated hybrid-capture HPV tests in detecting hrHPV and CIN2+/CIN3+. Despite its slightly suboptimal specificity, SureX HPV could be an alternative in primary screening due to its full genotyping capability.
背景：在设计良好、基于人群的筛查研究中评估新型人乳头瘤病毒（HPV）检测对于确保宫颈癌筛查的益处至关重要。方法：来自中国的8638名年龄在25岁以上的女性使用基于pcr的全基因分型HPV检测（SureX HPV）、混合捕获HPV检测（DH2/careHPV）和细胞学进行HPV筛查。如果有任何异常结果，则需要进行阴道镜检查和活检。评估宫颈上皮内瘤变2级及以上（CIN2+）和CIN3+的筛查效果。结果：SureX HPV检测的高危HPV （hrHPV）阳性率显著高于careHPV (11.0% vs. 8.2%, P < 0.05)，且显著高于细胞学（ASC-US+）检测CIN2+/CIN3+的阳性率（P < 0.05）。结论：基于pcr的SureX HPV检测在检测hrHPV和CIN2+/CIN3+方面与经过验证的混合捕获HPV检测具有良好的一致性。尽管其特异性略低于最佳水平，但由于其完整的基因分型能力，SureX HPV可作为初级筛查的替代方法。
{"title":"Clinical performance of the SureX PCR HPV test versus hybrid capture assays (DH2/careHPV) in primary cervical cancer screening","authors":"Yumei Ouyang , Guzhanuer Abuduxikuer , Tangnuer Abulimiti , Guligeina Abudurexiti , Qian Zhuo , Wenyun Li , Kadeliya Muhetaer , Shaliya Abuduwufu , Gulixian Tuerxun , Remila Rezhake , Guzhalinuer Abulizi","doi":"10.1016/j.tvr.2025.200319","DOIUrl":"10.1016/j.tvr.2025.200319","url":null,"abstract":"<div><h3>Background</h3><div>Evaluating novel human papillomavirus (HPV) tests in well-designed, population-based screening studies is essential for ensuring the benefits of cervical cancer screening.</div></div><div><h3>Methods</h3><div>8638 women aged over 25 years from China underwent HPV screening using a PCR-based full genotyping HPV assay (SureX HPV), alongside hybrid-capture HPV tests (DH2/careHPV) and cytology. Any abnormal results triggered colposcopy and biopsy if indicated. Screening performance was evaluated for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+.</div></div><div><h3>Results</h3><div>The high-risk HPV (hrHPV) positive rate by SureX HPV was significantly higher than by careHPV (11.0 % vs. 8.2 %, <em>P</em> <0.01) but similar to DH2 HPV (12.0 % vs. 11.5 %, <em>P</em> =0.34). The overall agreement rates between SureX HPV and careHPV/DH2 HPV were 93.5 % (Kappa=0.63) and 94.0 % (Kappa=0.71). For CIN2+ detection, SureX HPV showed not-significantly higher sensitivity than careHPV (91.2 % vs 82.5 %, <em>P</em> =0.18) but lower specificity (91.2 % vs. 93.1 %, <em>P</em> <0.01). Compared to DH2, SureX HPV demonstrated comparable sensitivity (95.7 % for both, <em>P</em> =1.0) and specificity (89.5 % vs. 90.2 %, <em>P</em> =0.21). Similar patterns were observed for CIN3+ detection. The area under the receiver operating characteristic curve (AUC) for the SureX HPV was similar to hybrid-capture HPV tests (<em>P</em> >0.05 for both) and significantly higher than the cytology (ASC-US+) test for CIN2+/CIN3+ detection (<em>P</em> <0.05 for both).</div></div><div><h3>Conclusions</h3><div>The PCR-based SureX HPV test demonstrated good concordance with well-validated hybrid-capture HPV tests in detecting hrHPV and CIN2+/CIN3+. Despite its slightly suboptimal specificity, SureX HPV could be an alternative in primary screening due to its full genotyping capability.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"19 ","pages":"Article 200319"},"PeriodicalIF":4.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-17DOI: 10.1016/j.tvr.2025.200318
Said Ali Yerim , Youssef Chami Khazraji , Rachid Bekkali , Maria Bennai , Nassiba Bahra , Imane Chaoui , Fatima Zahra Chellat , Zineb Gaizi , Nabil Tachfouti , Anas Benabdellah , Bouchra Belkadi , Mohammed Attaleb , Mohamed Amine Berraho , Mohammed El Mzibri
Recently, the World Health Organization recommended integrating HPV testing into cervical cancer screening programs globally. This study aimed to compare the GeneXpert assay with PCR-sequencing for HPV detection and genotyping to assess the feasibility of incorporating HPV molecular testing into cervical cancer screening. A total of 1000 women aged 30 or 40 from rural and urban areas across four regions in Morocco with high sexually transmitted infection prevalence were recruited. After excluding 21 invalid tests, DNA testing on the remaining 979 samples showed an HPV prevalence of 4.0 % (39/979) by PCR and 5.0 % (49/979) by Xpert, with an overall prevalence of 5.7 % (56/979) when combining both techniques. The concordance rate between the tests was 97.5 %. Notably, the Xpert HPV assay was highly efficient in detecting HPV, with nearly all identified HPVs being high-risk oncogenic types, predominantly HPV16, 18, 31, 35, and 45.
The Xpert HPV assay has demonstrated excellent analytical performance, making it a reliable option for HPV detection in vaginal and cervical swabs. Its integration into primary cervical cancer screening programs could significantly enhance the early detection of HPV-positive cases, thereby strengthening the screening framework and potentially reducing both the incidence and mortality of cervical cancer. Future studies should focus on confirming these results and exploring the utility of this method in conjunction with other diagnostic tools such as visual inspection with acetic acid (VIA) for a comprehensive assessment of its effectiveness in real-world settings.
{"title":"Evaluating the performance of the Xpert HPV assay in detecting HPV positive cases in Morocco","authors":"Said Ali Yerim , Youssef Chami Khazraji , Rachid Bekkali , Maria Bennai , Nassiba Bahra , Imane Chaoui , Fatima Zahra Chellat , Zineb Gaizi , Nabil Tachfouti , Anas Benabdellah , Bouchra Belkadi , Mohammed Attaleb , Mohamed Amine Berraho , Mohammed El Mzibri","doi":"10.1016/j.tvr.2025.200318","DOIUrl":"10.1016/j.tvr.2025.200318","url":null,"abstract":"<div><div>Recently, the World Health Organization recommended integrating HPV testing into cervical cancer screening programs globally. This study aimed to compare the GeneXpert assay with PCR-sequencing for HPV detection and genotyping to assess the feasibility of incorporating HPV molecular testing into cervical cancer screening. A total of 1000 women aged 30 or 40 from rural and urban areas across four regions in Morocco with high sexually transmitted infection prevalence were recruited. After excluding 21 invalid tests, DNA testing on the remaining 979 samples showed an HPV prevalence of 4.0 % (39/979) by PCR and 5.0 % (49/979) by Xpert, with an overall prevalence of 5.7 % (56/979) when combining both techniques. The concordance rate between the tests was 97.5 %. Notably, the Xpert HPV assay was highly efficient in detecting HPV, with nearly all identified HPVs being high-risk oncogenic types, predominantly HPV16, 18, 31, 35, and 45.</div><div>The Xpert HPV assay has demonstrated excellent analytical performance, making it a reliable option for HPV detection in vaginal and cervical swabs. Its integration into primary cervical cancer screening programs could significantly enhance the early detection of HPV-positive cases, thereby strengthening the screening framework and potentially reducing both the incidence and mortality of cervical cancer. Future studies should focus on confirming these results and exploring the utility of this method in conjunction with other diagnostic tools such as visual inspection with acetic acid (VIA) for a comprehensive assessment of its effectiveness in real-world settings.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"19 ","pages":"Article 200318"},"PeriodicalIF":4.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-20DOI: 10.1016/j.tvr.2025.200317
Julia Mai , Masih Nazari , Thomas Stamminger , Sabrina Schreiner
Daxx and HIRA are key proteins in the host response to DNA virus infections. Daxx is involved in apoptosis, transcription regulation, and stress responses. During DNA virus infections, Daxx helps modulate the immune response and viral progression. Viruses like adenoviruses and herpesviruses can exploit Daxx to evade immune detection, either by targeting it for degradation or inhibiting its function. Daxx also interacts with chromatin to regulate transcription, which viruses can manipulate to enhance their own gene expression and replication. HIRA is a histone chaperone and reported to be essential for chromatin assembly and gene regulation. It plays a critical role in maintaining chromatin structure and modulating gene accessibility. During DNA virus infection, HIRA influences chromatin remodeling, affecting both viral and host DNA accessibility, which impacts viral replication and gene expression. Additionally, the histone variant H3.3 is crucial for maintaining active chromatin states. It is incorporated into chromatin independently of DNA replication and is associated with active gene regions. During viral infections, H3.3 dynamics can be altered, affecting viral genome accessibility and replication efficiency. Overall, Daxx and HIRA are integral to orchestrating viral infection programs, maintaining latency and/or persistence, and influencing virus-induced transformation by modulating chromatin dynamics and host immune responses, making them significant targets for therapeutic strategies once fully understood. Here, we summarize various DNA viruses and their crosstalk with Daxx and HIRA.
{"title":"Daxx and HIRA go viral – How chromatin remodeling complexes affect DNA virus infection","authors":"Julia Mai , Masih Nazari , Thomas Stamminger , Sabrina Schreiner","doi":"10.1016/j.tvr.2025.200317","DOIUrl":"10.1016/j.tvr.2025.200317","url":null,"abstract":"<div><div>Daxx and HIRA are key proteins in the host response to DNA virus infections. Daxx is involved in apoptosis, transcription regulation, and stress responses. During DNA virus infections, Daxx helps modulate the immune response and viral progression. Viruses like adenoviruses and herpesviruses can exploit Daxx to evade immune detection, either by targeting it for degradation or inhibiting its function. Daxx also interacts with chromatin to regulate transcription, which viruses can manipulate to enhance their own gene expression and replication. HIRA is a histone chaperone and reported to be essential for chromatin assembly and gene regulation. It plays a critical role in maintaining chromatin structure and modulating gene accessibility. During DNA virus infection, HIRA influences chromatin remodeling, affecting both viral and host DNA accessibility, which impacts viral replication and gene expression. Additionally, the histone variant H3.3 is crucial for maintaining active chromatin states. It is incorporated into chromatin independently of DNA replication and is associated with active gene regions. During viral infections, H3.3 dynamics can be altered, affecting viral genome accessibility and replication efficiency. Overall, Daxx and HIRA are integral to orchestrating viral infection programs, maintaining latency and/or persistence, and influencing virus-induced transformation by modulating chromatin dynamics and host immune responses, making them significant targets for therapeutic strategies once fully understood. Here, we summarize various DNA viruses and their crosstalk with Daxx and HIRA.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"19 ","pages":"Article 200317"},"PeriodicalIF":4.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号