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

基本信息

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

项目摘要

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，全球十分之一以上的癌症是由病毒感染引起的，每年导致超过 130 万人死亡。人乳头瘤病毒 (HPV) 是造成这种病毒诱发的癌症负担的最重要因素之一。几乎一半的癌症都是由 HPV 感染引起的，包括宫颈癌和生殖器癌，以及口腔和咽喉癌。虽然 HPV 与癌症发生之间的因果关系已得到充分证实，但 HPV 感染中发生的导致 HPV 肿瘤形成的具体变化尚不清楚。了解这些变化非常重要，这样才能开发出治疗 HPV 感染和癌症的新疗法以及早期疾病检测的诊断工具。 HPV 有数百种不同类型，但其中只有极少数被世界卫生组织列为致癌物。 HPV 16 型导致大多数宫颈癌和口腔癌，而 HPV 18 型是宫颈癌第二常见的原因，但在口腔癌中很少发现。造成这种差异的原因尚不清楚，但我们假设 HPV 16 型和 18 型对不同解剖部位的宿主细胞有不同的操纵作用，从而导致观察到的临床结果差异。所有病毒都会操纵宿主细胞环境来增强感染性后代的产生。我们已经证明，在自然宿主细胞中建立 HPV 感染会显着改变宿主细胞基因子集的表达。这种 HPV 驱动的基因表达“重编程”是 HPV 感染持续存在的基础，而 HPV 感染是癌症发展的一个重要危险因素。重要的是，在持续性 HPV 感染的自然史早期发生的许多基因表达变化会增加受感染细胞的生长速度和寿命，因此很可能导致疾病进展。该提案中描述的实验旨在回答有关 HPV16 和 18 在口腔或宫颈正常感染中如何表现的长期存在的问题。我们将全面描述 HPV 诱导的基因表达变化的分子基础，并确定这些变化中哪些对于病毒在每个身体部位的持续存在和疾病进展很重要。使用癌细胞系和 HPV 相关肿瘤的临床样本，我们将探讨癌细胞生长是否需要新的病毒特异性变化，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急需的新见解，并确定导致疾病进展的病毒特异性事件。