Inactivation of the PRH/HHEX tumour suppressor and its effects on inflammatory signalling in prostate cancer.

前列腺癌是英国男性中最常见的癌症，这种疾病在非洲裔男性中发病率特别高。每年约有5万例新病例被诊断出来，随着男性寿命的延长，这一数字还在增加。大多数被诊断患有前列腺癌的男性并没有死于这种疾病。然而，对于疾病已经扩散到身体其他部位的患者，手术阉割是推荐的治疗方法。对于病情较轻的患者，放射治疗和/或药物治疗是有效的。然而，这些治疗可能有严重的副作用，包括骨质疏松症和骨折。在许多不太严重的病例中，治疗可能是不必要的，因为癌症不太可能进展和扩散。更好地识别需要治疗的患者和更好的治疗方法将对患者产生巨大的价值，并为NHS节省大量成本。在肯尼亚和其他低收入和中等收入国家，前列腺癌的发病率也在上升，在这些国家，治疗费用和这种疾病造成的生命损失是经济发展的主要障碍。该项目的目的是提高我们对前列腺癌进展原因的理解，并创建一个前列腺癌样本档案，这将对本研究和该领域的未来工作有价值。前列腺炎症很常见，这是前列腺癌的一个重要因素。LMIC和英国患者的前列腺炎症可能有多种原因，包括细菌和病毒感染以及自身免疫反应。来自免疫系统的细胞存在于前列腺中，在前列腺癌中，它们释放信号，增加癌细胞的复制和扩散能力。我们已经发现一种叫做PRH的蛋白质可以阻止前列腺细胞复制并阻止它们入侵其他组织。我们发现，随着前列腺癌的发展，PRH的活性以三种方式下降：首先，PRH蛋白被磷酸化修饰而失活；第二，正常产生PRH的基因停止产生PRH；第三，这个基因在一些癌细胞中被完全删除。我们的工作表明，PRH蛋白通过控制许多基因的活性来起作用，这些基因在允许前列腺细胞对免疫细胞的信号作出反应方面很重要，特别是我们发现PRH控制对某些类型的免疫细胞释放的一种叫做转化生长因子β (TGFb)的分子的反应。此外，我们已经证明TGFb本身通过减少PRH基因产生的PRH的数量和增加PRH的磷酸化来控制PRH的活性。我们将调查免疫细胞和免疫信号在肯尼亚和英国前列腺癌中的重要性，并找出PRH水平和活性的变化如何改变前列腺细胞对TGFb和其他免疫信号的反应。为了实现这一目标，我们将收集肯尼亚患者的血液、尿液和癌症样本，并通过问卷调查记录这些患者与前列腺癌相关的临床病史。然后，我们将使用一种叫做免疫组织化学（IHC）的技术来确定肯尼亚和英国前列腺癌样本中PRH和磷酸化PRH的水平，这种技术使我们能够可视化癌细胞中的蛋白质。我们还将测量肯尼亚血液样本中炎症信号和免疫细胞的水平。最后，我们将确定PRH水平和活性的变化如何影响前列腺细胞对免疫细胞信号的反应，以及这些信号如何控制PRH水平。这些研究将促进我们对免疫信号如何参与前列腺癌的理解。他们还将告诉我们，测量血液中的免疫信号水平和前列腺癌中的PRH或磷酸化的PRH是否可能是预测哪些患者需要治疗的好方法。

Prostate cancer is the most common cancer in men in the UK and this disease has a particularly high incidence in men of African origin. Around 50,000 new cases are diagnosed each year and this is increasing as men live longer. Most men diagnosed with prostate cancer do not die from this disease. However, for patients with disease that has spread to other sites in the body, surgical castration is the recommended treatment. For patients with less advanced disease radiotherapy and/or drug treatments are effective. However, these treatments can have serious side effects including osteoporosis and bone fracture. In many less advanced cases treatment is probably unnecessary as the cancer is very unlikely to progress and spread. Better ways of identifying patients who need treatment and better treatments would be of immense value to patients and result in major cost savings for the NHS. The incidence of prostate cancer in Kenya and other low- and middle-income countries (LMIC) is also rising and in these countries the cost of treatment and the cost of lives lost to this disease are major barriers to economic development. The aims of this project are to improve our understanding of the causes of prostate cancer progression and to create an archive of prostate cancer samples that will be of value to this study and to future work in this area.Inflammation in the prostate is common and this is known to be an important factor in prostate cancer. Inflammation in the prostate in LMIC and UK patients can have many causes including bacterial and viral infections and autoimmune responses. Cells from the immune system are found in the prostate and in prostate cancers they release signals that increase the replication of cancer cells and increase their ability to spread. We have discovered that a protein called PRH stops prostate cells from replicating and stops them from invading other tissues. We found that as prostate cancer becomes more advanced the activity of PRH is decreased in three ways: first, the PRH protein is inactivated by a modification known as phosphorylation; second, the gene that normally produces PRH is stopped from making PRH; and third, this gene is deleted altogether in some cancer cells. Our work showed that the PRH protein works by controlling the activity of many genes important in allowing prostate cells to respond to signals from immune cells and in particular we showed that PRH controls the response to a molecule called Transforming Growth Factor beta (TGFb) released from some types of immune cell. In addition we have shown that TGFb itself controls PRH activity by decreasing how much PRH is produced by the PRH gene and by increasing phosphorylation of PRH. We will investigate the importance of immune cells and immune signals in prostate cancer in Kenya and in the UK and find out how changes in the levels and activity of PRH alter the response of prostate cells to TGFb and other immune signals. To achieve this we will collect blood, urine, and cancer samples from Kenyan patients and document the clinical history associated with prostate cancer in these patients using questionnaires. We will then determine the levels of PRH and phosphorylated PRH in Kenyan and UK prostate cancer samples using a technique called immunohistochemistry (IHC) that allows us to visualise proteins in cancer cells. We will also measure the levels of inflammatory signals and immune cells in the Kenyan blood samples. Finally we will determine how changes in PRH levels and activity influence how prostate cells respond to signals from immune cells and how these signals control PRH levels. These studies will advance our understanding of how immune signals are involved in prostate cancer. They will also tell us whether measuring the levels of immune signals in blood and PRH or phosphorylated PRH in prostate cancer might be a good ways to predict which patients require treatment.