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Are different AP-1 subunit heterodimers associated with colorectal cancer patient outcome, metastasis and tumour hypoxia?

不同的 AP-1 亚基异二聚体与结直肠癌患者的预后、转移和肿瘤缺氧相关吗？

基本信息

批准号：
2605692
负责人：
金额：
--
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2605692
关键词：
different AP subunit heterodimers associated

项目摘要

Colorectal cancer is the third most common cancer leading to 500,000 deaths a year worldwide. Colorectal cancers frequently contain regions of low oxygen (hypoxia). Tumour hypoxia is caused by high proliferative rates and poor vascularisation. Tumour hypoxia is associated with therapy resistance, increased metastasis and worse patient survival. Identifying novel approaches to target hypoxic tumours is key to improving patient survival. We recently identified that AP-1 is a major regulator of hypoxic tumour survival and growth. AP-1 is a transcription factor formed by the heterodimerisation of FOS and JUN protein subunits. The function of these heterodimers is not interchangeable and target genes of the AP-1 heterodimers differ. AP-1 target genes regulate major hallmarks of cancer phenotypes. In this project we aim to quantify AP-1 heterodimer levels using a novel imaging approach that allows functional characterisation of protein states in patient tumour samples. We will identify which AP-1 heterodimers are associated with colorectal tumour hypoxia, metastasis and patient survival. We will also investigate the functional role of clinically relevant AP-1 subunits. We will use CRISPR CAS9 gene knockouts of AP-1 subunits in colorectal cancer cell lines and investigate cancer phenotypes including 3-Dimensional growth and tumour invasion.

结直肠癌是第三大常见癌症，每年在全球范围内导致50万人死亡。结肠直肠癌通常包含低氧（缺氧）区域。肿瘤缺氧是由高增殖率和不良的血管形成引起的。肿瘤缺氧与治疗抵抗、转移增加和患者存活率降低相关。确定靶向缺氧肿瘤的新方法是提高患者生存率的关键。我们最近发现AP-1是缺氧肿瘤存活和生长的主要调节因子。AP-1是由FOS和JUN蛋白亚基异源二聚化形成的转录因子。这些异二聚体的功能是不可互换的，并且AP-1异二聚体的靶基因不同。AP-1靶基因调节癌症表型的主要标志。在这个项目中，我们的目标是量化AP-1异二聚体水平使用一种新的成像方法，允许功能表征的蛋白质状态在患者肿瘤样本。我们将确定哪些AP-1异二聚体与结直肠肿瘤缺氧、转移和患者生存相关。我们还将研究临床相关的AP-1亚基的功能作用。我们将在结直肠癌细胞系中使用AP-1亚基的CRISPR CAS9基因敲除，并研究癌症表型，包括三维生长和肿瘤侵袭。