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PRH/HHEX in intrahepatic cholangiocarcinoma, disease progression and response to chemotherapeutics.

PRH/HHEX 在肝内胆管癌、疾病进展和化疗反应中的作用。

基本信息

批准号：
MR/N012615/1
负责人：
Padma-Sheela Jayaraman
金额：
$ 56.6万
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：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN012615%2F1
关键词：
PRH HHEX intrahepatic cholangiocarcinoma disease

项目摘要

Cholangiocarcinoma is cancer of the bile ducts that carry bile from the liver to the gall bladder and the small intestine. The number of cases of Cholangiocarcinoma is increasing year by year as is the number of deaths caused by this disease. There are several established risk factors for Cholangiocarcinoma including chronic Hepatitis B and C infection, autoimmune-related diseases such as Primary Sclerosing Cholangitis (PSC), and, in some countries, liver fluke infection. In most cases the disease is very advanced at the time of diagnosis and only around 30% of patients are suitable for surgery. New treatment options and biomarkers that allow early detection and/or inform personalised cancer treatment for individual patients are urgently needed. Under normal circumstances cell proliferation, cell-cell contacts and cell movement are carefully controlled and a large part this control is brought about by proteins called transcription factors that determine which genes are turned on or off in our cells and thereby determine how each cell behaves. We are studying a transcription factor called PRH/HHEX that is essential for liver and bile duct formation because this factor can inhibit many important pathways in the cell that are known to be required for cancer cell division and movement. In this project we will investigate the importance of PRH in cholangiocarcinoma. Using samples taken from patients with cholangiocarcinoma we have already shown that PRH levels are reduced in cholangiocarcinoma cells. The aim of this project is to investigate this in more detail using a larger number of samples. We will also identify genes that are regulated by PRH in cholangiocarcinoma cells and we will determine whether the products of these genes, or PRH itself, can be used as biomarkers to predict how quickly the cancer will progress or even allow us to identify people at risk of developing cholangiocarcinoma before they show symptoms of the disease. We will also determine whether changes in PRH activity alter the ability cholangiocarcinoma cells to form tumours in mice and we will examine whether changes in PRH these cells makes them more or less sensitive to drugs that are used to treat this disease. Finally we think that the re-establishment of PRH activity in cholangiocarcinoma could be a useful strategy for cancer treatment. We will test this using drugs that prevent protein modifications that we have previously shown to result in PRH inactivation and PRH degradation.

胆管癌是将胆汁从肝脏运送到胆囊和小肠的胆管的癌症。胆管癌的病例数逐年增加，因为这种疾病导致的死亡人数也在增加。胆管癌有几个确定的风险因素，包括慢性B和C型肝炎感染，自身免疫相关疾病，如原发性硬化性胆管炎（PSC），以及在一些国家，肝吸虫感染。在大多数情况下，疾病在诊断时非常晚期，只有大约30%的患者适合手术。迫切需要新的治疗选择和生物标志物，以允许早期检测和/或为个体患者提供个性化的癌症治疗。在正常情况下，细胞增殖、细胞间接触和细胞运动都受到严格控制，这种控制很大程度上是由一种称为转录因子的蛋白质实现的，这些转录因子决定了我们细胞中哪些基因被打开或关闭，从而决定了每个细胞的行为。我们正在研究一种称为PRH/HHEX的转录因子，它对肝脏和胆管的形成至关重要，因为这种因子可以抑制细胞中许多重要的通路，这些通路是癌细胞分裂和运动所必需的。在这个项目中，我们将探讨PRH在胆管癌中的重要性。使用从胆管癌患者中提取的样本，我们已经表明胆管癌细胞中PRH水平降低。该项目的目的是使用大量样本更详细地调查这一点。我们还将确定胆管癌细胞中受PRH调控的基因，并确定这些基因的产物或PRH本身是否可以用作生物标志物来预测癌症进展的速度，甚至允许我们在出现疾病症状之前识别有发展胆管癌风险的人。我们还将确定PRH活性的变化是否会改变胆管癌细胞在小鼠体内形成肿瘤的能力，并且我们将检查PRH这些细胞的变化是否会使它们对用于治疗这种疾病的药物更敏感或更不敏感。最后，我们认为，在胆管癌中重建PRH活性可能是一个有用的癌症治疗策略。我们将使用药物来测试这一点，这些药物可以防止我们以前已经证明会导致PRH失活和PRH降解的蛋白质修饰。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Misregulation of the proline rich homeodomain (PRH/HHEX) protein in cancer cells and its consequences for tumour growth and invasion.

DOI：
10.1186/s13578-016-0077-7
发表时间：
2016
期刊：
Cell & bioscience
影响因子：
7.5
作者：
Gaston K;Tsitsilianos MA;Wadey K;Jayaraman PS
通讯作者：
Jayaraman PS

Targeting protein kinase CK2 in the treatment of cholangiocarcinoma.

DOI：
10.37349/etat.2021.00055
发表时间：
2021
期刊：
Exploration of targeted anti-tumor therapy
影响因子：
0
作者：
通讯作者：

Proline-Rich Homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth.

DOI：
10.1038/oncsis.2017.42
发表时间：
2017-06-12
期刊：
Oncogenesis
影响因子：
6.2
作者：
Kershaw RM;Roberts D;Wragg J;Shaaban AM;Humphreys E;Halsall J;Price L;Bicknell R;Gaston K;Jayaraman PS
通讯作者：
Jayaraman PS

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects