Host cell reprogramming by oncogenic human papillomavirus

致癌人乳头瘤病毒对宿主细胞进行重编程

• 批准号: MR/T015985/1
• 负责人: Joanna Parish
• 金额: $ 58.51万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT015985%2F1
• 关键词: Host; cell; reprogramming; oncogenic; human

Viral infections are estimated to cause over 1 in 10 of all cancers, resulting in over 1.3 million deaths a year, worldwide. One of the most significant contributors to this virally-induced cancer burden are human papillomaviruses (HPV); HPV infections cause almost half of these cancers, including cancers of the uterine cervix and genitals, and oral cancers in the mouth and throat. While the causal link between HPV and the development of cancer is well established, the specific changes that occur in HPV infections that drive the formation of HPV tumours are not well understood. It is important to understand these changes so that new therapies to treat HPV infections and cancers, and diagnostic tools for early disease detection, can be developed. There are hundreds of distinct types of HPV, but only a very small number of these are classified by the World Health Organisation as carcinogenic. HPV type 16 causes the majority of cervical and oral cancers whereas HPV type 18 is the second most common cause of cervical cancer but is rarely found in oral cancers. The reasons for this disparity are unknown but we hypothesise that HPV types 16 and 18 differentially manipulate host cells at different anatomical sites resulting in the observed differences in clinical outcome. All viruses manipulate their host cell environment to enhance production of infectious progeny. We have shown that establishment of HPV infection in the natural host cells significantly alters the expression of a subset of host cell genes. This HPV-driven gene expression 'reprogramming' is fundamental to persistence of HPV infection, a significant risk factor for cancer development. Importantly, many of the gene expression changes that occur early in the natural history of persistent HPV infections increase the growth rate and life span of the infected cells, and therefore are very likely contribute to disease progression. The experiments described in this proposal are designed to answer long-standing questions about how HPV16 and 18 behave in a normal infection of the oral cavity or uterine cervix. We will fully characterise the molecular basis of HPV-induced gene expression changes and determine which of these changes are important for viral persistence and disease progression at each body site. Using cancer cell lines and clinical samples of HPV-associated tumours, we will explore whether novel virus-specific changes are required for cancer cell growth and sustained in HPV-driven tumours. These experiments will provide much needed novel insight into the normal life cycle of HPV infections at clinically relevant body sites and identify virus-specific events that drive disease progression.

据估计，全世界十分之一以上的癌症是由病毒感染引起的，每年导致130多万人死亡。病毒引起的癌症负担最重要的因素之一是人乳头瘤病毒(HPV)；HPV感染导致了近一半的癌症，包括子宫颈癌和生殖器癌，以及口腔和喉癌。虽然HPV与癌症发展之间的因果联系已经得到很好的证实，但在HPV感染中发生的推动HPV肿瘤形成的具体变化还没有很好地了解。重要的是要了解这些变化，以便开发治疗HPV感染和癌症的新疗法，以及早期发现疾病的诊断工具。HPV有数百种不同的类型，但只有极少数被世界卫生组织归类为致癌物质。HPV16型是导致大多数宫颈癌和口腔癌的原因，而HPV18型是导致宫颈癌的第二大常见原因，但在口腔癌中很少发现。这种差异的原因尚不清楚，但我们假设，HPV16型和18型在不同的解剖部位对宿主细胞进行不同的操作，从而导致观察到的临床结果的差异。所有的病毒都会操纵它们的宿主细胞环境，以增加感染性后代的产生。我们已经证明，在自然宿主细胞中建立HPV感染显著改变了宿主细胞基因的子集的表达。这种由HPV驱动的基因表达“重新编程”是HPV感染持续存在的基础，HPV感染是癌症发展的一个重要风险因素。重要的是，在持续性HPV感染的自然历史早期发生的许多基因表达变化增加了感染细胞的生长速度和寿命，因此很可能有助于疾病的进展。这项提案中描述的实验旨在回答长期存在的问题，即HPV16和18型在正常的口腔或宫颈感染中表现如何。我们将充分描述HPV诱导的基因表达变化的分子基础，并确定这些变化中的哪些对每个身体部位的病毒持久性和疾病进展是重要的。利用癌细胞株和HPV相关肿瘤的临床样本，我们将探索癌细胞生长是否需要新的病毒特异性改变，并在HPV驱动的肿瘤中持续存在。这些实验将为临床相关身体部位的HPV感染的正常生命周期提供亟需的新见解，并确定推动疾病进展的病毒特异性事件。

项目成果

CTCF regulates hepatitis B virus cccDNA chromatin topology

CTCF 调节乙型肝炎病毒 cccDNA 染色质拓扑

• DOI: 10.1101/2023.09.06.556185
• 发表时间: 2023
• 作者: Dobrica M

The CCCTC-binding factor CTCF represses hepatitis B virus Enhancer I and regulates viral transcription

CCCTC 结合因子 CTCF 抑制乙型肝炎病毒增强子 I 并调节病毒转录

• DOI: 10.1101/2020.05.08.085548
• 发表时间: 2020
• 作者: D'Arienzo V

The chromatin insulator CTCF regulates HPV18 transcript splicing and differentiation-dependent late gene expression

染色质绝缘子 CTCF 调节 HPV18 转录物剪接和分化依赖性晚期基因表达

• DOI: 10.1101/2021.04.30.442078
• 发表时间: 2021
• 作者: Ferguson J

The chromatin insulator CTCF regulates HPV18 transcript splicing and differentiation-dependent late gene expression.

• DOI: 10.1371/journal.ppat.1010032
• 发表时间: 2021-11
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Ferguson J;Campos-León K;Pentland I;Stockton JD;Günther T;Beggs AD;Grundhoff A;Roberts S;Noyvert B;Parish JL
• 通讯作者: Parish JL

Lead Time to Recurrence After Posttreatment Plasma and Saliva HPV DNA Testing in Patients With Low-Risk HPV Oropharynx Cancer

• DOI: 10.1001/jamaoto.2023.1730
• 发表时间: 2023-07-27
• 期刊: JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY
• 影响因子: 7.8
• 作者: Califano，Joseph;Yousef，Andrew;Mehanna，Hisham
• 通讯作者: Mehanna，Hisham