The Role of Progranulin in Cholangiocarcinoma Growth

描述（由申请人提供）：肝内和肝外胆管上皮细胞（胆管细胞）的肿瘤转化引起胆管癌，这是一种预后极差的毁灭性癌症。早期诊断是困难的，因为症状通常是由于胆管阻塞而出现的，并且对当前化疗的相对抵抗使得诊断后的预期寿命较短。因此，控制胆管癌细胞生长的研究对于设计更有效的治疗策略势在必行。我们已经获得了新的初步数据表明，有一个过度生产的生长因子progranulin在胆管癌细胞和组织，因此，表明该因子可能在胆管癌的进展中发挥作用。本提案的总体目标是确定颗粒蛋白前体上调的分子机制，并确定颗粒蛋白前体产生增加对细胞生长的影响。我们提出的工作将集中在两个特定的目标，已被设计用于测试以下假设：1）在胆管癌中，由于通过ERK 1/2/RSK/C/EBP（-依赖性途径）异常表达IL-6，颗粒蛋白前体被上调。2)颗粒蛋白前体通过IP 3/Ca 2？FOXO 1转录活性的依赖性抑制。阐明的机制，其中颗粒蛋白前体的生产增加，胆管癌细胞生长的结果增加颗粒蛋白前体水平将是重要的了解胆管癌的病因，并可能发挥至关重要的作用，在发展中的治疗策略，用于治疗胆管癌。 公共卫生相关性：胆管癌是一种毁灭性的胆道癌症，预后差，治疗选择有限。本申请的健康相关性在于，剖析可能导致胆管细胞（胆管树的细胞）恶性转化为胆管癌的机制最终有望提供对胆管癌原因的理解，并增加开发用于治疗这种致命癌症的新型治疗方案的机会。

DESCRIPTION (provided by applicant): Neoplastic transformation of intra- and extra-hepatic biliary epithelial cells (cholangiocytes), gives rise to cholangiocarcinoma, a devastating cancer that has a very poor prognosis. Early diagnosis is difficult as symptoms usually arise as a result of bile duct blockage and relative resistance to current chemotherapies makes for a short life expectancy after diagnosis. Therefore, research into the control of cholangiocarcinoma cell growth is imperative to design more effective treatment strategies. We have obtained novel preliminary data indicating that there is an over production of the growth factor progranulin in cholangiocarcinoma cells and tissue and thus, suggest that this factor may play a role in the progression of cholangiocarcinoma. The overall objective of this proposal is to determine the molecular mechanisms by which progranulin is upregulated and to determine the consequences of increased progranulin production on cell growth. Our proposed work will focus on two specific aims that have been designed to test the following hypotheses: 1) Progranulin is upregulated in cholangiocarcinoma as a result of aberrant IL-6 expression via an ERK1/2/RSK/C/EBP(-dependent pathway. 2) Progranulin has growth promoting properties on cholangiocarcinoma via the IP3/Ca2?dependent inhibition of FOXO1 transcriptional activity. The elucidation of the mechanism by which progranulin production is increased in cholangiocarcinoma and the consequences of the increased progranulin levels on cholangiocarcinoma cell growth will be important in understanding the etiology of cholangiocarcinoma and may play a paramount role in the development of therapeutic strategies for the treatment of cholangiocarcinoma. PUBLIC HEALTH RELEVANCE: Cholangiocarcinoma is a devastating cancer of the biliary tract that has poor prognosis and limited treatment options. The health relatedness of this application is that dissecting the mechanisms that may be responsible for the malignant transformation of cholangiocytes (cells that line the biliary tree) into cholangiocarcinoma can ultimately be expected to provide understanding of the causes of cholangiocarcinoma and increase opportunities for the development of novel treatment regimes for the treatment of this deadly cancer.