Tumour Virus Research最新文献

英文中文

Drosophila model of HPV18-Induced pathogenesis reveals a role for E6 oncogene in regulation of NF-κB and Wnt to inhibit apoptosis hpv18诱导的果蝇模型揭示E6致癌基因调控NF-κB和Wnt抑制细胞凋亡

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2025-03-10 DOI: 10.1016/j.tvr.2025.200316

Mojgan Padash Barmchi , Rami N. Hassan , Mehrnaz Afkhami , John P. Masly , Harrison Brown , Quincy P. Collins , Michael J. Grunsted

Cancers caused by high-risk human papillomavirus (HPV) remain a significant health threat resulting in more than 300,000 deaths, annually. Persistent expression of two HPV oncogenes, E6 and E7, are necessary for cancer development and progression. E6 has several functions contributing to tumorigenesis one of which is blocking programmed cell death, apoptosis. The detailed mechanism of anti-apoptosis function of E6 is not fully understood. Here, using a Drosophila model of HPV18E6 and the human UBE3A-induced pathogenesis, we show that anti-apoptotic function of E6 is conserved in Drosophila. We demonstrate that the Drosophila homologs of human NF-κB transcription factors, Dorsal and Dif are proapoptotic. They induce the expression of Wingless (Wg, the Drosophila homolog of human Wnt), leading to apoptosis. Our results indicate that E6 oncogene inhibits apoptosis by downregulating the expression of Wg, Dorsal, and Dif. Additionally, we find that Dorsal and Dif, not only promote apoptosis but also regulate autophagy and necrosis. Dorsal promotes autophagy while Dif counteracts it, inducing the formation of acidic vacuoles and necrosis. Interestingly, although E6 blocks the proapoptotic function of Dorsal and Dif, it lacks the ability to interfere with their role in apoptosis-independent cell death. Given the high conservation of NF-κB transcription factors our results provide new insight into potential mechanisms mediated by NF-κB to intervene with cell immortalization action of E6 oncoprotein in HPV-infected cells.

由高风险人类乳头瘤病毒（HPV）引起的癌症仍然是一个重大的健康威胁，每年造成30多万人死亡。两种HPV癌基因E6和E7的持续表达是癌症发生和发展所必需的。E6在肿瘤发生中具有多种功能，其中之一是阻断程序性细胞死亡和细胞凋亡。E6抗细胞凋亡作用的具体机制尚不完全清楚。本研究利用果蝇HPV18E6模型和人类ube3a诱导的发病机制，我们发现E6的抗凋亡功能在果蝇中是保守的。我们证明了人类NF-κB转录因子Dorsal和Dif在果蝇中的同源物具有促凋亡作用。它们诱导无翼蛋白（Wnt，人类Wnt的果蝇同源物）的表达，导致细胞凋亡。我们的研究结果表明，E6癌基因通过下调Wg、Dorsal和Dif的表达来抑制细胞凋亡。此外，我们发现Dorsal和Dif不仅能促进细胞凋亡，还能调节细胞自噬和坏死。Dorsal促进自噬，而Dif抵消自噬，诱导酸性液泡的形成和坏死。有趣的是，尽管E6阻断了Dorsal和Dif的促凋亡功能，但它无法干扰它们在凋亡非依赖性细胞死亡中的作用。鉴于NF-κB转录因子的高度保守性，我们的研究结果为NF-κB介导的干预hpv感染细胞中E6癌蛋白永活作用的潜在机制提供了新的见解。

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引用次数: 0

Regulation of epithelial growth factor receptors by the oncoprotein E5 during the HPV16 differentiation-dependent life cycle 肿瘤蛋白E5在HPV16分化依赖生命周期中对上皮生长因子受体的调控

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2025-03-07 DOI: 10.1016/j.tvr.2025.200315

Mariano A. Molina , Sneha Biswas , Omar Jiménez-Vázquez , Jason M. Bodily

Human papillomavirus (HPV) 16 infection initiates upon viral entry into the basal cells of the epithelium. The virus manipulates signaling pathways to complete its life cycle, which depends on cellular differentiation. The virus expresses the oncoproteins E5, E6, and E7 to promote immune evasion, cell cycle progression, apoptosis inhibition, and viral replication. The least studied viral oncoprotein is E5 (16E5), which can regulate epithelial growth factor receptor (GFR) signaling pathways. GFRs such as transforming growth factor-beta receptor (TGFBR), epidermal growth factor receptor (EGFR), and keratinocyte growth factor receptor (KGFR) have essential roles in cell growth, differentiation, and proliferation. These receptors obtain their ligands from the microenvironment, and once activated, regulate cellular behavior in the epithelium. GFRs therefore represent valuable targets for the virus to establish and maintain a cellular environment supportive of infection. The ability of 16E5 to regulate proliferation and differentiation varies through the differentiating epithelium, making it necessary to adequately describe the association between 16E5 and GFRs. Here we summarize the regulation of GFR signaling pathways by 16E5, discuss the roles of stromal growth factors, and outline unresolved questions over cellular differentiation and proliferation during the HPV life cycle.

人乳头瘤病毒（HPV） 16感染开始时，病毒进入上皮基底细胞。病毒操纵信号通路来完成它的生命周期，这取决于细胞分化。该病毒表达癌蛋白E5、E6和E7，促进免疫逃避、细胞周期进展、细胞凋亡抑制和病毒复制。研究最少的病毒癌蛋白是E5 (16E5)，它可以调节上皮生长因子受体（GFR）信号通路。转化生长因子-受体（TGFBR）、表皮生长因子受体（EGFR）和角质细胞生长因子受体（KGFR）等gfr在细胞生长、分化和增殖中起着重要作用。这些受体从微环境中获得配体，一旦被激活，就会调节上皮细胞的行为。因此，gfr是病毒建立和维持有利于感染的细胞环境的宝贵靶标。16E5调节增殖和分化的能力因分化上皮而异，因此有必要充分描述16E5与gfr之间的关系。本文总结了16E5对GFR信号通路的调控，讨论了基质生长因子的作用，并概述了HPV生命周期中细胞分化和增殖的未解决问题。

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引用次数: 0

De-regulation of aurora kinases by oncogenic HPV; implications in cancer development and treatment 致瘤性HPV对极光激酶的去调控作用对癌症发展和治疗的影响。

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2025-02-07 DOI: 10.1016/j.tvr.2025.200314

Kemi Hannah Oladipo , Joanna L. Parish

Human papillomaviruses (HPVs) cause diseases ranging from benign warts to invasive cancers. HPVs are the cause of almost all cervical cancers and a sub-set of other epithelial malignancies including head and neck cancers, specifically within the oropharynx. The oncogenic properties of HPV are largely mediated through the viral oncoproteins E6 and E7, which disrupt many cellular pathways to drive uncontrolled cell proliferation. One family of proteins targeted by HPV is the Aurora kinase family. Aurora kinases are serine/threonine kinases including Aurora kinase A (AURKA), B (AURKB), and C (AURKC) which are often dysregulated in many cancer types, including HPV driven cancers. All three family members play essential roles in mitotic regulation and accurate cell division.

The deregulation of Aurora kinases by HPV infection highlights their potential as therapeutic targets in HPV-associated malignancies. Targeting Aurora kinase activity, in combination with current HPV therapies, may provide new avenues for treating HPV-induced cancers and reducing the burden of HPV-related diseases. Combinatorial inhibition targets distinct but overlapping functions of these kinases, thereby reducing the potential for cancer cells to develop resistance. This broad impact emphasizes the capability for Aurora kinase inhibitors not only as anti-mitotic agents but also as modulators of multiple oncogenic pathways. This review explores the combinatorial effects of Aurora kinase inhibition, offering insights into novel therapeutic strategies for the treatment of HPV-driven cancers.

人乳头瘤病毒（hpv）引起从良性疣到侵袭性癌症的各种疾病。人乳头状瘤病毒是几乎所有宫颈癌和包括头颈癌在内的其他上皮恶性肿瘤的亚群的原因，特别是在口咽部。HPV的致癌特性主要是通过病毒癌蛋白E6和E7介导的，它们破坏了许多细胞通路，从而驱动不受控制的细胞增殖。HPV靶向的一个蛋白家族是极光激酶家族。极光激酶是丝氨酸/苏氨酸激酶，包括极光激酶A （AURKA）、B （AURKB）和C (AURKC)，它们在许多癌症类型中经常失调，包括HPV驱动的癌症。这三个家族成员在有丝分裂调控和精确的细胞分裂中发挥重要作用。人乳头瘤病毒感染对极光激酶的抑制作用突出了它们作为人乳头瘤病毒相关恶性肿瘤治疗靶点的潜力。靶向极光激酶活性，结合目前的HPV治疗，可能为治疗HPV诱导的癌症和减轻HPV相关疾病的负担提供新的途径。组合抑制针对这些激酶的不同但重叠的功能，从而减少癌细胞产生耐药性的可能性。这种广泛的影响强调了极光激酶抑制剂的能力，不仅作为抗有丝分裂剂，而且作为多种致癌途径的调节剂。这篇综述探讨了极光激酶抑制的组合效应，为hpv驱动的癌症的治疗提供了新的治疗策略。

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引用次数: 0

How can HPV E6 manipulate host cell differentiation process to maintain the reservoir of infection HPV E6如何操纵宿主细胞分化过程以维持感染库。

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2025-01-19 DOI: 10.1016/j.tvr.2025.200313

Yuwen Chen , Nagayasu Egawa , Ke Zheng , John Doorbar

引用次数: 0

Rapid-onset cancer 迅速发生癌症。

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2025-01-02 DOI: 10.1016/j.tvr.2024.200312

Andrea Bilger, Paul F. Lambert

Human cancers are generally thought to develop over the course of decades. Such slow progression is well documented for a variety of cancers that we designate “slow-onset” cancers. “Rapid-onset” cancers, in contrast, can develop in a matter of months in humans or in as little as 9 days in mice. These cancers often develop under conditions that might be expected to accelerate cancer development: early development, immune deficiency, or viral infection. We will discuss rapid-onset cancers in the context of the "hallmarks of cancer" – properties cells must acquire in order to become malignant – focusing on how viruses are particularly well suited to causing rapid-onset cancer.

人类癌症通常被认为是在几十年的过程中形成的。这种缓慢的进展在我们称为“慢发”癌症的各种癌症中都有充分的记录。相比之下，“快速发作”的癌症在人类身上可以在几个月内发展，在老鼠身上可以在短短9天内发展。这些癌症通常在可能加速癌症发展的条件下发展：早期发展，免疫缺陷或病毒感染。我们将在“癌症特征”的背景下讨论快速发作的癌症——细胞必须获得的特性才能变成恶性的——重点关注病毒如何特别适合引起快速发作的癌症。

引用次数: 0

Too many cooks in the kitchen: HPV driven carcinogenesis – The result of collaboration or competition? 厨房里的厨师太多：HPV驱动的致癌作用——是合作还是竞争的结果？

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2024-12-27 DOI: 10.1016/j.tvr.2024.200311

Weimer Kathleen

Infection by Human Papillomaviruses accounts for the most widespread sexually transmitted infection worldwide. Clinical presentation of these infections can range from subclinical and asymptomatic to anogenital cancers, with the latter associated with persistent infection over a significant period of time. Of the over 200 isotypes of the human virus identified, a subset of these has been characterized as high-risk due to their ability to induce oncogenesis. At the core of Papillomavirus pathogenesis sits three virally encoded oncoproteins: E5, E6, and E7. In this review we will discuss the respective roles of these proteins and how they contribute to carcinogenesis, evaluating key distinguishing features that separate them from their low-risk counterparts. Furthermore, we will consider the complex relationship between this trio and how their interwoven functional networks underpin the development of cancer.

人乳头瘤病毒感染是世界范围内最广泛的性传播感染。这些感染的临床表现可以从亚临床和无症状到肛门生殖器癌，后者与持续感染相当长的一段时间有关。在已确定的200多种人类病毒同型中，其中一部分因其诱导肿瘤发生的能力而被定性为高风险。乳头瘤病毒发病机制的核心是三种病毒编码的癌蛋白：E5、E6和E7。在这篇综述中，我们将讨论这些蛋白质各自的作用以及它们如何促进致癌，评估将它们与低风险对应物区分开来的关键区别特征。此外，我们将考虑这三者之间的复杂关系，以及它们相互交织的功能网络如何支撑癌症的发展。

引用次数: 0

Editorial: Tumour Virus Research on Virus Host Interactions and Cell Transformation 社论：肿瘤病毒在病毒宿主相互作用和细胞转化方面的研究。

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2024-12-20 DOI: 10.1016/j.tvr.2024.200310

Lawrence Banks, Peter Stern

引用次数: 0

Drugs and drug targets for the treatment of HPV-positive cervical cancer 治疗hpv阳性子宫颈癌的药物和药物靶点。

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2024-12-19 DOI: 10.1016/j.tvr.2024.200309

Carly A. Burmeister, Saif F. Khan, Sharon Prince

Cervical cancer is primarily driven by persistent infection with high-risk human papillomavirus (HPV) strains and remains a significant global health challenge, particularly in low- and middle-income countries where late-stage diagnoses is common. While vaccination and screening programs have reduced incidence rates, the need for novel and more effacacious and cost-effective therapeutic options is therefore critical especially for advanced cervical cancer. This review highlights several key advances in the understanding of HPV-induced carcinogenesis and the development of therapeutic strategies over the past five years. Important areas of focus include the role of HPV oncoproteins E5, E6 and E7 in modulating signalling pathways, treatment strategies for precancerous lesions, the potential of natural compounds to target cervical cancer cells, and the emergence of immunotherapies, checkpoint inhibitors, antibody-drug conjugates, and novel drug combinations to treat cervical cancer. Additionally, lifestyle recommendations and the integration of natural supplements are discussed for their potential to enhance treatment efficacy and improve patient outcomes. The developments reported in this review underscore the evolving landscape of cervical cancer treatment and the need for continued research to validate and integrate these emerging therapies into clinical practice.

宫颈癌主要是由高风险人乳头瘤病毒（HPV）株的持续感染引起的，仍然是一个重大的全球卫生挑战，特别是在晚期诊断很常见的低收入和中等收入国家。虽然疫苗接种和筛查项目降低了发病率，但对新颖、更有效和更具成本效益的治疗方案的需求至关重要，特别是对晚期宫颈癌。这篇综述强调了在过去五年中对hpv诱导的癌变的理解和治疗策略的发展方面的几个关键进展。重点领域包括HPV癌蛋白E5， E6和E7在调节信号通路中的作用，癌前病变的治疗策略，天然化合物靶向宫颈癌细胞的潜力，以及免疫疗法，检查点抑制剂，抗体-药物偶联物和新型药物组合治疗宫颈癌的出现。此外，还讨论了生活方式建议和天然补充剂的整合，以提高治疗效果和改善患者预后的潜力。本综述中报道的进展强调了宫颈癌治疗的发展前景，以及继续研究以验证这些新兴疗法并将其纳入临床实践的必要性。

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引用次数: 0

Intraperitoneal delivery of cannabidiol (CBD) and Δ9-tetrahydocannabinol (THC) promotes papillomavirus infections in athymic nude mice 腹腔注射大麻二酚（CBD）和Δ9-tetrahydocannabinol （THC）促进乳突裸鼠乳头瘤病毒感染。

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2024-12-16 DOI: 10.1016/j.tvr.2024.200307

Sarah A. Brendle , Jingwei Li , Dongxiao Sun , Junjia Zhu , Angela N. Henderson-Redmond , Daniel J. Morgan , Karla K. Balogh , Danielle Covington , Debra A. Shearer , Jiafen Hu

We used our mouse papillomavirus (MmuPV1) model to test the hypothesis that two primary psychoactive ingredients of marijuana, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), promote papillomavirus persistence in the oral mucosa of infected mice. We conducted intraperitoneal (ip) injections of a moderate dose (3 mg/kg) of either CBD and/or THC in both male and female athymic nude mice and followed the mice up to 20 weeks post-infection. These doses are comparable to what is estimated for human conventional cannabis consumption. All mice were infected with MmuPV1 in the oral cavity at week 4 post-ip delivery of CBD, THC, or a combination of THC and CBD (T + C). THC and CBD were detected in the blood of treated mice for up to 72 h after ip injection. Significantly higher levels of viral DNA were detected in males from both CBD and T + C-treated groups compared to those in the control group at 9- 10-and 12-weeks post infection. A marginally increased viral RNA was also detected in the infected tongues of males in all tested groups compared to that in males in the vehicle control group; the opposite was observed in females. We detected significantly higher levels of dermal dendritic cells (CD205⁺CD11c⁺), granulocytes (Ly6G⁺), but macrophages (F4-80+) recruited to the infected tongues of CBD-treated females. Our findings suggest that CBD may play a role in promoting MmuPV1 persistence in the oral cavity.

我们使用小鼠乳头瘤病毒（MmuPV1）模型来验证大麻的两种主要精神活性成分Δ9-tetrahydrocannabinol （THC）和大麻二酚（CBD）促进乳头瘤病毒在感染小鼠口腔黏膜中的持续存在的假设。我们对雄性和雌性胸腺裸小鼠进行了中等剂量（3mg /kg）的CBD和/或THC腹腔注射，并随访小鼠至感染后20周。这些剂量与估计的人类传统大麻消费量相当。所有小鼠在注射CBD、四氢大麻酚或四氢大麻酚和CBD联合（T+C）后第4周在口腔感染MmuPV1。注射ip后72小时，在治疗小鼠血液中检测到THC和CBD。在感染后9- 10周和12周，与对照组相比，在CBD和T+ c治疗组的男性中检测到的病毒DNA水平明显更高。与载体对照组相比，在所有测试组的男性感染舌头中检测到的病毒RNA也略有增加；在女性身上观察到的情况正好相反。我们检测到真皮树突状细胞（CD205+CD11c+）、粒细胞（Ly6G+）水平明显升高，但巨噬细胞（F4-80+）被招募到经cbd治疗的雌性感染舌头上。我们的研究结果表明，CBD可能在促进mupv1在口腔中的持久性中发挥作用。

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Clinical indications for host-cell DNA methylation markers in cervical screening and management of cervical intraepithelial neoplasia: A review 宫颈上皮内瘤变筛查和治疗中宿主细胞DNA甲基化标志物的临床适应症综述

IF 4.7 Q1 VIROLOGY

Tumour Virus Research

Pub Date : 2024-12-16 DOI: 10.1016/j.tvr.2024.200308

S. Dick , D.A.M. Heideman , J. Berkhof , R.D.M. Steenbergen , M.C.G. Bleeker

DNA methylation of host-cell genes is an epigenetic process that regulates gene expression and is associated with cervical cancer development. Studies on the natural history of cervical intraepithelial neoplasia (CIN) and the molecular alterations associated with cervical carcinogenesis led to the identification of several host-cell DNA methylation markers. Over the past years, various studies on methylation markers have shown promising results in terms of diagnostic and prognostic value to improve cervical cancer screening and management of CIN. This review provides an overview of the clinical indications of host-cell DNA methylation markers in cervical screening and management of CIN, and outlines avenues for further applications.

宿主细胞基因的DNA甲基化是一种调控基因表达的表观遗传过程，与宫颈癌的发展有关。对宫颈上皮内瘤变（CIN）的自然史和与宫颈癌发生相关的分子改变的研究导致了几种宿主细胞DNA甲基化标记物的鉴定。近年来，关于甲基化标志物的各种研究在改善宫颈癌CIN筛查和管理方面的诊断和预后价值方面显示出令人鼓舞的结果。本文综述了宿主细胞DNA甲基化标志物在宫颈CIN筛查和管理中的临床适应症，并概述了进一步应用的途径。

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