The TAZ transcriptional co-activator as a type specific arbiter of HPV driven cervical cancer

TAZ 转录共激活因子作为 HPV 驱动的宫颈癌的类型特异性仲裁者

• 批准号: MR/X009564/1
• 负责人: Andrew Macdonald
• 金额: $ 82.66万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX009564%2F1
• 关键词: TAZ; transcriptional; co; activator; type

Despite excellent vaccines, long term infection with so-called 'high-risk' human papillomaviruses (HPV) is the cause of 5% of the global cancer burden (~600,000 cancers per year). These cancers include nearly all cervical cancers, other cancers of the ano-genital tract (anal, vaginal, penile) and a growing number of oral cancers. These cancers predominantly impact on low and middle income countries, where the death rate can be 18 times higher than in developed countries. Limited vaccine availability in low income countries, vaccine hesitancy in developed countries and the lag between infection and disease ensures that the burden of HPV-associated disease remains high. As such, HPV still represents a major burden in many clinical settings and new therapies are desperately needed to complement the existing vaccines.HPVs must re-wire the cells they infect to create an environment in which they can reproduce and establish a long-term infection. As a parasite, the virus needs to take over the host cell machinery for this to happen. Understanding which host cell factors are vital for the virus to reproduce and to cause disease may help us to identify targets for new therapies.We have identified that the expression of the host protein TAZ is increased in HPV infected cells. TAZ controls gene expression and its expression and activity are often uncontrolled in cancers. Despite this, we do not fully understand how TAZ works, how it is regulated and which host genes it switches on or off. Our data shows that HPV needs TAZ to be switched in order for cervical cancer cells to grow. In this project we will aimTo understand how TAZ expression is increased, how TAZ functions in cervical cancer cells and which host gene products are important in cervical cancers. Our work will have impact in terms of helping us to understand which host factors are important for HPV-driven diseases and more broadly we will uncover new knowledge about how host proteins contribute to cancer.

尽管有出色的疫苗，但所谓“高风险”人乳头瘤病毒 (HPV) 的长期感染仍是造成全球 5% 癌症负担的原因（每年约 600,000 例癌症）。这些癌症包括几乎所有宫颈癌、其他肛门生殖道癌症（肛门癌、阴道癌、阴茎癌）以及越来越多的口腔癌。这些癌症主要影响低收入和中等收入国家，这些国家的死亡率可能比发达国家高 18 倍。低收入国家的疫苗供应有限、发达国家对疫苗犹豫不决以及感染与疾病之间的滞后性导致 HPV 相关疾病的负担仍然很高。因此，HPV 在许多临床环境中仍然是一个主要负担，迫切需要新的疗法来补充现有疫苗。HPV 必须重新连接它们感染的细胞，以创造一个可以繁殖并建立长期感染的环境。作为一种寄生虫，病毒需要接管宿主细胞机制才能实现这一点。了解哪些宿主细胞因子对于病毒繁殖和引起疾病至关重要，可能有助于我们确定新疗法的靶点。我们已经发现，宿主蛋白 TAZ 的表达在 HPV 感染的细胞中增加。 TAZ 控制基因表达，其表达和活性在癌症中通常不受控制。尽管如此，我们还不完全了解 TAZ 是如何工作的、它是如何调节的以及它打开或关闭哪些宿主基因。我们的数据显示，HPV 需要转换 TAZ 才能使宫颈癌细胞生长。在这个项目中，我们将旨在了解TAZ表达如何增加、TAZ如何在宫颈癌细胞中发挥作用以及哪些宿主基因产物在宫颈癌中很重要。我们的工作将有助于我们了解哪些宿主因素对于 HPV 驱动的疾病很重要，更广泛地说，我们将发现有关宿主蛋白如何导致癌症的新知识。