The Role of Progranulin in Cholangiocarcinoma Growth

颗粒体蛋白前体在胆管癌生长中的作用

• 批准号: 7870645
• 负责人: Sharon DeMorrow
• 金额: $ 7.15万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870645
• 关键词: Biliary; Biliary Tract Cancer; Binding; Boxing; CCAAT-Enhancer-Binding Proteins; Cell Line; Cell Proliferation; Cells; Cholangiocarcinoma; Data; Development; Diagnosis; Early Diagnosis; Epithelial Cells; Etiology; Event; Gene Expression; Genes; Goals; Growth; Growth Factor; Health; Hepatic; IL6 Signaling Pathway; Interleukin-6; Life Expectancy; Malignant - descriptor; Malignant Neoplasms; Mitogen-Activated Protein Kinase 3; Molecular; Neoplastic Cell Transformation; PGRN gene; Pathway interactions; Play; Production; Progranulin; Property; RPS6KA gene; Recombinants; Relative (related person); Research; Resistance; Role; Signal Transduction; Symptoms; Testing; Tissues; Transcriptional Regulation; Tumor Cell Invasion; Work; base; bile duct; biliary tract; cell growth; chemotherapy; cholangiocyte; design; effective therapy; forkhead protein; neoplastic cell; novel; outcome forecast; promoter; public health relevance; research study; ribosomal protein S6 kinase 2; therapeutic development; transcription factor; treatment strategy; tumor growth

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.

描述（由申请人提供）：肿瘤内和肝外胆道上皮细胞（胆管细胞）的肿瘤转化会引起胆管癌，这是一种毁灭性的癌症，预后较差。早期诊断很困难，因为症状通常是由于胆管阻塞而引起的，并且对当前化学疗法的相对耐药性会在诊断后短暂预期寿命。因此，对胆管癌细胞生长的控制的研究对于设计更有效的治疗策略至关重要。我们已经获得了新的初步数据，表明胆管癌细胞和组织中生长因子易生肽的过度产生，因此表明该因子可能在胆管癌的进展中起作用。该提案的总体目的是确定易生蛋白上调的分子机制，并确定促进蛋白增加对细胞生长的后果。我们提出的工作将集中在旨在测试以下假设的两个特定目标上：1）由于异常IL-6表达通过ERK1/2/RSK/C/C/EBP表达的胆管癌中，胆管蛋白蛋白会上调。 FOXO1转录活动。阐明胆管癌中促进素蛋白产生的机制以及在胆管癌细胞生长中增加的胆管蛋白水平增加对理解胆管癌的病因的影响至关重要，并可能在治疗胆管瘤治疗的治疗策略的发展中起着至关重要的作用。 公共卫生相关性：胆管癌是胆道的毁灭性癌症，预后较差，治疗方案有限。该应用的健康相关性是，剖析可能导致胆管细胞（将胆道树扎在胆管癌中）恶性转化的机制最终可以预期，可以期望对胆管癌瘤的原因提供理解，并增加治疗方案的这种治疗方法的机会。