The Role of Progranulin in Cholangiocarcinoma Growth

描述(申请人提供)：肝内外胆管上皮细胞(胆管细胞)的肿瘤性转化，导致胆管细胞癌，这是一种预后非常差的毁灭性癌症。早期诊断很困难，因为症状通常是由于胆管阻塞而出现的，而且对目前化疗的相对抵抗会导致确诊后预期寿命较短。因此，研究控制胆管癌细胞生长势在必行，以设计更有效的治疗策略。我们获得了新的初步数据，表明在胆管癌细胞和组织中存在生长因子原颗粒的过度产生，因此，该因子可能在胆管癌细胞的进展中发挥作用。这项建议的总体目标是确定PRO上调的分子机制，并确定PRO产生增加对细胞生长的影响。我们的工作将集中在两个特定的目标上，这两个目标旨在检验以下假设：1)通过ERK1/2/RSK/C/EBP(依赖于ERK1/2/RSK/C/EBP)的途径，由于IL-6的异常表达，原颗粒在胆管癌细胞中上调。2)原颗粒通过IP3/Ca~(2+)依赖性抑制FOXO1转录活性，对胆管癌细胞具有促生长作用。阐明胆管癌细胞原颗粒生成增加的机制以及原颗粒水平升高对胆管癌细胞生长的影响将对了解胆管癌细胞的病因具有重要意义，并可能对胆管细胞癌的治疗策略的制定起到至关重要的作用。 公共卫生相关性：胆管癌是一种毁灭性的胆道癌，预后很差，治疗选择有限。这项应用与健康相关的是，解剖可能导致胆管细胞(排列在胆管树上的细胞)向胆管癌细胞恶性转化的机制，最终有望提供对胆管癌病因的了解，并增加开发治疗这种致命癌症的新治疗方案的机会。

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.