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

胆管癌是胆管的癌症，胆管将胆汁从肝脏输送到胆囊和小肠。胆管癌的病例数逐年增加，由这种疾病引起的死亡人数也逐年增加。胆管癌有几个确定的危险因素，包括慢性乙型肝炎和丙型肝炎感染，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，该病在诊断时已经非常晚期，只有约30%的患者适合手术治疗。目前迫切需要新的治疗方案和生物标志物，以便及早发现和/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，这种控制在很大程度上是由一种叫做转录因子的蛋白质实现的，这种蛋白质决定了细胞中哪些基因是开启的，哪些基因是关闭的，从而决定了每个细胞的行为。我们正在研究一种被称为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途径，这些途径已知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。利用胆管癌患者的样本，我们已经证明胆管癌细胞中的PRH水平降低。这个项目的目的是使用更多的样本来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，我们将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的进展速度，甚至允许我们在出现疾病症状之前识别有患胆管癌风险的人。我们还将确定PRH活性的变化是否会改变小鼠胆管癌细胞形成肿瘤的能力，我们将检查PRH的变化是否会使这些细胞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活性可能是一种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之前展示的导致PRH失活和PRH降解的蛋白质修饰。

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.