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The imprint of viral oncoproteins on the variable clinical behavior among human papilloma virus-related oropharyngeal squamous cell carcinomas. 病毒癌蛋白对人类乳头瘤病毒相关口咽鳞状细胞癌不同临床表现的影响。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-11-01 DOI: 10.1016/j.tvr.2024.200295
Malay K Sannigrahi, Lovely Raghav, Ahmed Diab, Devraj Basu

Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are variable in their progression, immune landscape, treatment responses, and clinical outcomes. Their behavior is impacted not only by differences in host genomic alterations but also by diversity in levels and activity of HPV-encoded oncoproteins. Striking differences in HPV mRNA levels are found among HPV+ OPSCCs and likely derive in part from variations in the structurally diverse mix of integrated and episomal HPV genomes they often contain. Viral oncoprotein levels and function are also impacted by differential splicing of the two long polycistronic transcripts of HPV16, the HPV type within most HPV+ OPSCCs. Further variation in viral oncoprotein function arises from the distinct lineages and sub-lineages of HPV16, which encode polymorphisms in functionally important portions of oncogenes. Here we review the limited current knowledge linking HPV mRNA expression and splicing to differences in oncoprotein function that likely influence OPSCC behavior. We also summarize the evolving understanding of HPV16 physical genome state and genetic variants and their potential contributions to HPV oncoprotein levels and function. Addressing considerable remaining challenges in defining the quantitative and qualitative imprint of HPV oncoproteins on each OPSCC holds promise to guide personalization of therapy for this disease.

人乳头状瘤病毒相关(HPV+)口咽鳞状细胞癌(OPSCC)在病情进展、免疫状况、治疗反应和临床结果方面各不相同。它们的行为不仅受到宿主基因组改变差异的影响,还受到HPV编码的癌蛋白水平和活性多样性的影响。HPV+ OPSCCs的HPV mRNA水平存在显著差异,部分原因可能是它们通常包含的整合和外显子HPV基因组结构多样。HPV16是大多数HPV+ OPSCC中的HPV类型,其两个长的多聚体转录本的剪接差异也会影响病毒肿瘤蛋白的水平和功能。病毒癌蛋白功能的进一步变化来自于HPV16的不同系和亚系,它们在癌基因的重要功能部分编码了多态性。在此,我们回顾了目前将 HPV mRNA 表达和剪接与可能影响 OPSCC 行为的肿瘤蛋白功能差异联系起来的有限知识。我们还总结了对 HPV16 物理基因组状态和遗传变异及其对 HPV 肿瘤蛋白水平和功能的潜在贡献的不断发展的认识。在确定 HPV 癌症蛋白对每种 OPSCC 的定量和定性影响方面仍存在大量挑战,解决这些挑战有望为这种疾病的个性化治疗提供指导。
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引用次数: 0
Genomic diversity of HPV6 and HPV11 in recurrent respiratory papillomatosis: Association with malignant transformation in the lungs and clinical outcomes 复发性呼吸道乳头状瘤病中 HPV6 和 HPV11 的基因组多样性:与肺部恶性转化和临床结果的关系
IF 4.7 Q1 VIROLOGY Pub Date : 2024-10-29 DOI: 10.1016/j.tvr.2024.200294
Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation.
We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing.
Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the NLRP1 gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts.
HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.
复发性呼吸道乳头状瘤病(RRP)是一种罕见的增殖性疾病,由人类乳头状瘤病毒 6(HPV6)和 HPV11 引起。我们应用高通量测序技术分析了 5 名恶性转化 RRP 患者和 4 名高度复发性非恶性 RRP 患者的不同时期样本。在两名患者中发现了HPV6和HPV11的一过性多重感染,后来又转变为单一感染。各组的病毒基因组载量相同(中位数 = 每个人类基因组 78 个病毒基因组)。在患者内部,我们没有观察到乳头状瘤病变和恶性组织中病毒序列的差异。对 NLRP1 基因的遗传分析表明,没有发现与特发性 RRP 相关的已知变异,但一些新型变异值得在更大的群体中进行研究。RRP可发生多重感染,但对于特定基因型而言,患者体内的病毒多样性极少。我们的研究结果证实了病毒基因型在疾病预后中的重要性,而且越来越多的证据表明,HPV11感染与年轻患者的RRP恶性转化有不同程度的关联。
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引用次数: 0
The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity SV40 病毒增强子是一种具有潜在致瘤活性的体细胞突变靶向元件
IF 4.7 Q1 VIROLOGY Pub Date : 2024-10-28 DOI: 10.1016/j.tvr.2024.200293
Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.
猿猴病毒 40(SV40)是一种猴病毒,在啮齿类动物中具有致瘤潜能,与包括淋巴瘤在内的几种人类癌症有关。一种相关的梅克尔细胞多瘤病毒通过表达截短的大肿瘤抗原(LT)导致人类患癌,截短抗原是由 APOBEC 家族的胞苷脱氨酶诱导突变引起的。AID(活化诱导胞苷脱氨酶)是 APOBEC 家族的成员之一,是抗体多样化过程(即体细胞高突变)的启动器,其异常表达和靶向是淋巴瘤发生的一个常见来源。在这项研究中,我们研究了 AID 是否会导致 SV40 LT 发生突变。我们证明,SV40增强子在几种细胞类型中具有很强的体细胞超突变靶向活性,AID诱导的突变在B细胞和肾细胞的SV40 LT中积累,并导致B细胞中LT表达截短。我们的研究结果表明,SV40增强子靶向LT的体细胞超突变能力是LT截短事件的潜在来源,而LT截短事件可能会导致各种细胞类型的肿瘤发生,从而通过一种新的突变途径将SV40感染与恶性发展联系起来。
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引用次数: 0
Opportunities to advance cervical cancer prevention and care 推进宫颈癌预防和护理的机遇
IF 4.7 Q1 VIROLOGY Pub Date : 2024-10-25 DOI: 10.1016/j.tvr.2024.200292
Cervical cancer (CaCx) is a major public health issue, with over 600,000 women diagnosed annually. CaCx kills someone every 90 s, mostly in low- and middle-income countries. There are effective yet imperfect mechanisms to prevent CaCx. Since human papillomavirus (HPV) infections cause most CaCx, they can be prevented by vaccination. Screening methodologies can identify premalignant lesions and allow interventions before a CaCx develops. However, these tools are less feasible in resource-poor environments. Additionally, current screening modalities cannot triage lesions based on their relative risk of progression, which results in overtreatment. CaCx care relies heavily on genotoxic agents that cause severe side effects. This review discusses ways that recent technological advancements could be leveraged to improve CaCx care and prevention.
宫颈癌(CaCx)是一个重大的公共卫生问题,每年有 60 多万妇女确诊患上宫颈癌。每 90 秒就有一人死于宫颈癌,主要发生在中低收入国家。目前已有有效但不完善的机制来预防 CaCx。由于人类乳头瘤病毒(HPV)感染是大多数 CaCx 的病因,因此可以通过接种疫苗来预防。筛查方法可以发现癌前病变,并在 CaCx 发生之前进行干预。然而,在资源匮乏的环境中,这些工具的可行性较低。此外,目前的筛查方法无法根据病变发展的相对风险对病变进行分流,从而导致过度治疗。CaCx治疗严重依赖会产生严重副作用的基因毒性药物。本综述将讨论如何利用最新的技术进步来改善 CaCx 的治疗和预防。
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引用次数: 0
A new role for human papillomavirus 16 E2: Mitotic activation of the DNA damage response to promote viral genome segregation 人类乳头瘤病毒 16 E2 的新作用:有丝分裂激活 DNA 损伤反应,促进病毒基因组分离。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.tvr.2024.200291

Human papillomaviruses (HPV) are causative agents in around 5% of all human cancers. To identify and develop new targeted HPV therapeutics we must enhance our understanding of the viral life cycle and how it interacts with the host. The HPV E2 protein dimerizes and binds to 12bp target sequences in the viral genome and segregates the viral genome during mitosis. In this function, E2 binds to the viral genome and the host chromatin simultaneously, ensuring viral genomes reside in daughter nuclei following cell division. We have demonstrated that a mitotic interaction between E2 and the DNA damage response (DDR) protein TOPBP1 is required for E2 segregation function. In non-infected cells, following DNA damage, TOPBP1 is recruited to the mitotic host genome via interaction with MDC1 and this interaction protects DNA integrity during mitosis. Recently we demonstrated that the E2-TOPBP1 interaction activates the DNA damage response (DDR) during mitosis independently from external stimuli, promoting TOPBP1 interaction with mitotic chromatin and therefore segregation of the viral genome. Therefore, the virus has hijacked an existing host mechanism in order to segregate the viral genome. This intricate E2 function will be described and discussed.

人类乳头瘤病毒(HPV)是约 5%人类癌症的致病因子。为了确定和开发新的人乳头瘤病毒靶向治疗药物,我们必须加强对病毒生命周期及其如何与宿主相互作用的了解。HPV E2 蛋白会二聚化并与病毒基因组中的 12bp 目标序列结合,并在有丝分裂过程中分离病毒基因组。在这一功能中,E2 同时与病毒基因组和宿主染色质结合,确保病毒基因组在细胞分裂后驻留在子核中。我们已经证明,E2与DNA损伤应答(DDR)蛋白TOPBP1之间的有丝分裂相互作用是E2分离功能所必需的。在非感染细胞中,DNA损伤后,TOPBP1通过与MDC1的相互作用被招募到有丝分裂宿主基因组,这种相互作用在有丝分裂过程中保护了DNA的完整性。最近我们证明,E2-TOPBP1 相互作用激活了有丝分裂过程中的 DNA 损伤反应(DDR),而不受外部刺激的影响,促进了 TOPBP1 与有丝分裂染色质的相互作用,从而促进了病毒基因组的分离。因此,病毒劫持了宿主现有的机制来分离病毒基因组。本文将对这一错综复杂的 E2 功能进行描述和讨论。
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引用次数: 0
HBx integration in diffuse large B-cell lymphoma inhibits Caspase-3-PARP related apoptosis 弥漫大 B 细胞淋巴瘤中的 HBx 整合可抑制与 Caspase-3-PARP 相关的细胞凋亡。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.tvr.2024.200290

Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma, and is closely associated with hepatitis B virus (HBV) infection status and hepatitis B X (HBx) gene integration. This project investigated the cellular biological effects and molecular mechanisms responsible for lymphomagenesis and the progression of HBx integration in DLBCL. The data showed that clinical DLBCL cells demonstrated HBx integration, and the sequencing analysis of integrated sites validated HBx integration in the constructed HBx-transfected cells. Compared with control cells, HBx-transfected cells had a significantly reduced proportion of mitochondrial membrane potential, signals of chromosomal DNA breaks, and proportion of apoptotic cells. Further studies found that this decreased apoptosis level was associated with a significant reduction of cleaved Caspase-3 and downstream poly ADP-ribose polymerase (PARP) proteins, revealing the molecular mechanisms of HBx-associated apoptosis in DLBCL. Animal experiments also demonstrated that the protein expression of cleaved Caspase-3 and PARP was prominently reduced in HBx-transfected cells from subcutaneous tumors in mice. Furthermore, the HBx-integrated cells in clinical tissues had significantly lower cleaved PARP levels than the HBx-negative samples. Therefore, HBx integration inhibits cell apoptosis through the Caspase-3-PARP pathway in DLBCL indicating a potential biomarker and therapeutic target in HBV related DLBCL.

弥漫大B细胞淋巴瘤(DLBCL)是非霍奇金淋巴瘤中最常见的病理类型,与乙型肝炎病毒(HBV)感染状态和乙型肝炎X(HBx)基因整合密切相关。该项目研究了 DLBCL 中淋巴瘤发生和 HBx 整合进展的细胞生物学效应和分子机制。数据显示,临床 DLBCL 细胞表现出 HBx 整合,整合位点的测序分析验证了 HBx 整合在构建的 HBx 转染细胞中。与对照细胞相比,HBx转染细胞的线粒体膜电位比例、染色体DNA断裂信号和凋亡细胞比例均显著降低。进一步研究发现,细胞凋亡水平的降低与裂解的Caspase-3和下游聚ADP-核糖聚合酶(PARP)蛋白的显著减少有关,揭示了HBx相关DLBCL细胞凋亡的分子机制。动物实验也表明,在小鼠皮下肿瘤的 HBx 转染细胞中,Caspase-3 和 PARP 的蛋白表达显著减少。此外,临床组织中的 HBx 整合细胞的裂解 PARP 水平明显低于 HBx 阴性样本。因此,HBx整合通过Caspase-3-PARP途径抑制DLBCL中的细胞凋亡,这表明HBV相关DLBCL是一种潜在的生物标记物和治疗靶点。
{"title":"HBx integration in diffuse large B-cell lymphoma inhibits Caspase-3-PARP related apoptosis","authors":"","doi":"10.1016/j.tvr.2024.200290","DOIUrl":"10.1016/j.tvr.2024.200290","url":null,"abstract":"<div><p>Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma, and is closely associated with hepatitis B virus (HBV) infection status and <em>hepatitis B X</em> (<em>HBx</em>) gene integration. This project investigated the cellular biological effects and molecular mechanisms responsible for lymphomagenesis and the progression of <em>HBx</em> integration in DLBCL. The data showed that clinical DLBCL cells demonstrated <em>HBx</em> integration, and the sequencing analysis of integrated sites validated <em>HBx</em> integration in the constructed HBx-transfected cells. Compared with control cells, HBx-transfected cells had a significantly reduced proportion of mitochondrial membrane potential, signals of chromosomal DNA breaks, and proportion of apoptotic cells. Further studies found that this decreased apoptosis level was associated with a significant reduction of cleaved Caspase-3 and downstream poly ADP-ribose polymerase (PARP) proteins, revealing the molecular mechanisms of HBx-associated apoptosis in DLBCL. Animal experiments also demonstrated that the protein expression of cleaved Caspase-3 and PARP was prominently reduced in HBx-transfected cells from subcutaneous tumors in mice. Furthermore, the <em>HBx</em>-integrated cells in clinical tissues had significantly lower cleaved PARP levels than the <em>HBx</em>-negative samples. Therefore, <em>HBx</em> integration inhibits cell apoptosis through the Caspase-3-PARP pathway in DLBCL indicating a potential biomarker and therapeutic target in HBV related DLBCL.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000144/pdfft?md5=3ffb604d2a76191481057e06101dce0d&pid=1-s2.0-S2666679024000144-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The impact of DNA tumor viruses in low-to-middle income countries (LMICS): A literature review DNA 肿瘤病毒对中低收入国家(LMICS)的影响:文献综述。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-07-06 DOI: 10.1016/j.tvr.2024.200289

DNA viruses are common in the human population and act as aetiological agents of cancer on a large scale globally. They include the human papillomaviruses (HPV), Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis viruses, and human polyomaviruses. Oncogenic viruses employ different mechanisms to induce cancer. Notably, cancer only develops in a minority of individuals who are infected, usually following protracted years of chronic infection. The human papillomaviruses (HPVs) are associated with the highest number of cancer cases, including cervical cancer and other epithelial malignancies. Hepatitis B virus (HBV) and the RNA virus hepatitis C (HCV) are significant contributors to hepatocellular cancer (HCC). Other oncoviruses include Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpes virus (KSHV), human T-cell leukemia virus (HTLV-I), and Merkel cell polyomavirus (MCPyV). The identification of these infectious agents as aetiological agents for cancer has led to reductions in cancer incidence through preventive interventions such as HBV and HPV vaccination, HPV-DNA based cervical cancer screening, antiviral treatments for chronic HBV and HCV infections, and screening of blood for transfusion for HBV and HCV. Successful efforts to identify additional oncogenic viruses in human cancer may provide further understanding of the aetiology and development of cancer, and novel approaches for prevention and treatment. Cervical cancer, caused by HPV, is the leading gynaecological malignancy in LMICs, with high age-standardised incidence and mortality rates, HCC due to HBV is an important cause of cancer deaths, and the burden of other cancer attributable to infections continues to rise globally. Hence, cancers attributable to DNA viruses have become a significant global health challenge. These viruses hence warrant continued attention and interrogation as efforts to understand them further and device further preventive interventions are critical.

DNA 病毒在人类中很常见,是全球范围内大规模癌症的病原体。它们包括人类乳头瘤病毒(HPV)、爱泼斯坦-巴氏病毒(EBV)、卡波西肉瘤相关疱疹病毒(KSHV)、肝炎病毒和人类多瘤病毒。致癌病毒采用不同的机制诱发癌症。值得注意的是,癌症只发生在少数感染者身上,通常是在长年慢性感染之后。人类乳头状瘤病毒(HPV)与最多的癌症病例有关,包括宫颈癌和其他上皮恶性肿瘤。乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)是导致肝细胞癌(HCC)的重要因素。其他肿瘤病毒包括爱泼斯坦-巴尔病毒(EBV)、卡波西肉瘤相关疱疹病毒(KSHV)、人类 T 细胞白血病病毒(HTLV-I)和梅克尔细胞多瘤病毒(MCPyV)。确定这些传染性病原体是癌症的病原体后,通过采取预防性干预措施,如接种 HBV 和 HPV 疫苗、进行基于 HPV DNA 的宫颈癌筛查、对慢性 HBV 和 HCV 感染进行抗病毒治疗,以及对输血进行 HBV 和 HCV 筛查,降低了癌症发病率。成功识别人类癌症中的其他致癌病毒可进一步了解癌症的病因和发展,并提供新的预防和治疗方法。由人类乳头瘤病毒(HPV)引起的宫颈癌是低收入和中等收入国家的主要妇科恶性肿瘤,其年龄标准化发病率和死亡率都很高;由乙型肝炎病毒(HBV)引起的肝转移癌是癌症死亡的重要原因之一;全球因感染引起的其他癌症的负担也在持续上升;因此,DNA 病毒引起的癌症已成为全球健康的重大挑战。因此,这些病毒值得持续关注和研究,因为进一步了解这些病毒并采取进一步的预防干预措施至关重要。
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引用次数: 0
DNA methylation at individual CpG-sites of EPB41L3, HTERT and FAM19A4 are useful for detection of cervical high-grade squamous intraepithelial lesions (HSIL) or worse: Analysis of individual CpG-sites outperforms averaging EPB41L3、HTERT和FAM19A4的单个CpG位点的DNA甲基化有助于检测宫颈高级别鳞状上皮内病变(HSIL)或更严重的病变:对单个 CpG 位点的分析优于平均分析。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-07-01 DOI: 10.1016/j.tvr.2024.200288
Monica Molano , Dorothy A. Machalek , Samuel Phillips , Grace Tan , Suzanne M. Garland , David Hawkes , Prisha Balgovind , Reza Haqshenas , Steve G. Badman , John Bolnga , Josephine Gabuzzi , Zure Kombati , Gloria M. Munnull , Julia ML. Brotherton , Marion Saville , John M. Kaldor , Pamela J. Toliman , Andrew J. Vallely , Gerald L. Murray

Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.

Methylation of EPB41L3 (1–6 CpG-sites), hTERT (1–10 CpG-sites) and FAM19A4 (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for FAM19A4 directed to the first exon region not explored previously.

In clinician-collected samples, methylation at CpG-sites 4 and 5 of EPB41L3 were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of EPB41L3 sites 2/4 plus FAM19A4 site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].

Methylation at CpG-site 5 of FAM19A4 was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of FAM19A4 for cancer (0.77). Combined, FAM19A4 site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.

In conclusion, methylation at individual CpG-sites of EPB41L3 and FAM19A4 outperformed global analysis and improved HSIL+ detection, warranting further investigation.

基因启动子的全局甲基化分析有望用于检测高危人类乳头瘤病毒(hrHPV)阳性妇女的高级别或更严重的鳞状上皮内病变(HSIL+)。然而,单个 CpG 位点甲基化数据的诊断性能有限。我们对巴布亚新几内亚自采样本和临床医生采集样本中预测 HSIL+ 的甲基化情况进行了研究。通过对 44 份 HPV+样本(4 例癌症、19 例 HSIL、4 例低度鳞状上皮内病变 (LSIL)、17 例正常样本)进行热测序,评估了 EPB41L3(1-6 个 CpG 位点)、hTERT(1-10 个 CpG 位点)和 FAM19A4(1-5 个 CpG 位点)的甲基化情况。针对 FAM19A4 设计了新的引物,引物指向以前未探究过的第一个外显子区域。在临床医生采集的样本中,EPB41L3的CpG位点4和5的甲基化是预测HSIL的最佳指标(AUC>0.83),CpG位点4是预测癌症的最佳指标(0.925)。EPB41L3 2/4位点和FAM19A4 1位点的组合是最佳的HSIL+标记物[敏感性100%,特异性63.2%]。在自采样本中,FAM19A4 的 CpG 位点 5 的甲基化是预测 HSIL 的最佳指标(0.67),而 FAM19A4 的 CpG 位点 1 和 3 则是预测癌症的最佳指标(0.77)。结合 FAM19A4 位点 1 和 HPV 16/18 检测,灵敏度为 82.6%,特异性为 61.9%。总之,EPB41L3 和 FAM19A4 单个 CpG 位点的甲基化优于全局分析,提高了 HSIL+ 的检测率,值得进一步研究。
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引用次数: 0
HPV16 genome structure analysis in oropharyngeal cancer PDXs identifies tumors with integrated and episomal genomes 口咽癌 PDX 中的 HPV16 基因组结构分析确定了具有整合基因组和外显子基因组的肿瘤。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-06-25 DOI: 10.1016/j.tvr.2024.200285
Claire D. James , Raymonde O. Otoa , Aya H. Youssef , Christian T. Fontan , Malay K. Sannigrahi , Brad Windle , Devraj Basu , Iain M. Morgan

HPV + oropharyngeal squamous cell carcinoma (OPC) incidence recently surpassed cervical cancer and is the most common HPV-related cancer in the developed world. HPV16 is in ∼90 % of HPV + OPCs, with episomal genomes in the majority of cases. Most existing HPV16+ cancer cell lines derive from outside the oropharynx and harbor integrated HPV genomes. Thus, there is need for OPC preclinical models to evaluate standard and experimental therapeutics in the presence of episomal HPV16 oncogenic drivers. Here we characterize HPV genome structures in eight HPV16+ OPC patient-derived xenografts (PDXs), and evaluate their responses to standard chemotherapy. HPV genome state was investigated by combining Southern blot, T5 exonuclease assay, whole genome sequencing, and RNAseq data. This analysis revealed complexity and variation in integrated vs. episomal HPV forms across PDXs and demonstrated that four PDXs predominantly contain episomal HPV16. Episomal status did not ensure favorable in vivo responses to cisplatin therapy, despite the more favorable prognosis previously attributed to episomal HPV + tumors; this could be due to the small number present in the dataset. Our analysis establishes PDX models as test platforms for novel therapies designed to target maintenance of the episomal forms of HPV16 that commonly appear in OPC.

人乳头瘤病毒+口咽鳞状细胞癌(OPC)的发病率最近超过了宫颈癌,成为发达国家最常见的人乳头瘤病毒相关癌症。90%的HPV+口咽鳞状细胞癌中都含有HPV16,大多数病例中都含有外显子基因组。现有的大多数HPV16+癌细胞系来自口咽部以外的部位,并携带整合的HPV基因组。因此,有必要建立口咽癌临床前模型,以评估外显子HPV16致癌驱动因子存在时的标准和实验疗法。在这里,我们描述了 8 个 HPV16+ OPC 患者衍生异种移植物(PDXs)的 HPV 基因组结构,并评估了它们对标准化疗的反应。我们结合 Southern 印迹、T5 外切酶测定、全基因组测序和 RNAseq 数据对 HPV 基因组状态进行了研究。这项分析揭示了PDXs中整合型与表观型HPV的复杂性和差异,并证明有四个PDXs主要含有表观型HPV16。尽管表型 HPV + 肿瘤的预后较好,但表型状态并不能确保对顺铂治疗产生良好的体内反应;这可能是由于数据集中的肿瘤数量较少。我们的分析结果表明,PDX 模型可作为新型疗法的测试平台,这些疗法的目标是维持通常出现在 OPC 中的 HPV16 表观形式。
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引用次数: 0
Viral miRNA delivered by exosomes from Marek's disease virus-transformed lymphoma cell line exerts regulatory function in internalized primary chicken embryo fibroblast cells 马雷克氏病病毒转化的淋巴瘤细胞系外泌体传递的病毒 miRNA 在内化的原代鸡胚成纤维细胞中发挥调控功能。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-06-22 DOI: 10.1016/j.tvr.2024.200286
Man Teng , Jun Luo , Yaoyao Zhang , Vishwanatha R.A.P. Reddy , Priya Samuel , Yongxiu Yao , Venugopal Nair

In the past decade, research has demonstrated that viral miRNAs encoded by a number of viral genomes, particularly by most of the herpesvirus including Marek's disease virus (MDV), play important regulatory roles in viral infection, replication, and regulation of tumorigenesis. As macrovesicles in cells, exosomes can deliver viral miRNAs and exert gene regulatory functions. Whether the exosomes play a role in the replication, pathogenesis/tumorigenesis of avian herpesviruses such as oncogenic Marek's disease virus (MDV) remains unclear. Herein we extracted and identified the exosomes from MDV-transformed T cell line MSB-1 and demonstrated high abundance of MDV-1 miRNA expression. Using dual luciferase-based reporter assay, we also demonstrated that the exosomes derived from MSB-1 can deliver functional miRNA successfully into primary chicken embryo fibroblasts. These findings provide new insights into the role of exosomes and the mechanisms of how virus-encoded miRNA function in MDV latency/activation switching, viral replication, pathogenesis and/or tumorigenesis.

过去十年的研究表明,一些病毒基因组编码的病毒 miRNA,特别是包括马立克氏病病毒(MDV)在内的大多数疱疹病毒编码的病毒 miRNA,在病毒感染、复制和调控肿瘤发生中发挥着重要的调控作用。作为细胞中的大囊泡,外泌体可传递病毒 miRNA 并发挥基因调控功能。外泌体是否在禽类疱疹病毒(如致癌的马立克氏病病毒(MDV))的复制、致病机理/肿瘤发生中发挥作用仍不清楚。在此,我们从经 MDV 转化的 T 细胞系 MSB-1 中提取并鉴定了外泌体,并证明了 MDV-1 miRNA 的高丰度表达。我们还利用基于荧光素酶的双重报告实验证明,从 MSB-1 提取的外泌体能成功地将功能性 miRNA 运送到原代鸡胚成纤维细胞中。这些发现为了解外泌体的作用以及病毒编码的miRNA如何在MDV潜伏/激活转换、病毒复制、致病和/或肿瘤发生中发挥作用的机制提供了新的视角。
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Tumour Virus Research
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