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: 8073604
• 负责人: Sharon DeMorrow
• 金额: $ 6.24万
• 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/8073604
• 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; 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 Pathway; 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）：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，这是一种预后非常差的破坏性癌症。早期诊断很困难，因为症状通常是由于胆管堵塞而出现，并且对当前化疗的相对抵抗导致诊断后的预期寿命较短。因此，研究控制胆管癌细胞生长以设计更有效的治疗策略势在必行。我们获得了新的初步数据，表明胆管癌细胞和组织中生长因子颗粒体蛋白前体的过量产生，因此表明该因子可能在胆管癌的进展中发挥作用。该提案的总体目标是确定颗粒体蛋白前体上调的分子机制，并确定颗粒体蛋白前体产量增加对细胞生长的影响。我们提出的工作将集中于两个具体目标，旨在测试以下假设：1) 由于通过 ERK1/2/RSK/C/EBP(依赖性途径) 异常 IL-6 表达，颗粒体蛋白前体在胆管癌中上调2) 颗粒体蛋白前体通过 IP3/Ca2+ 依赖性抑制 FOXO1 转录活性，具有促进胆管癌生长的特性。阐明胆管癌中颗粒体蛋白前体产生增加的机制以及颗粒体蛋白前体水平增加对胆管癌细胞生长的影响对于了解胆管癌的病因学非常重要，并且可能在制定治疗胆管癌的治疗策略中发挥重要作用。胆管癌。 公众健康相关性：胆管癌是一种破坏性的胆道癌症，预后不良，治疗选择有限。该应用的健康相关性在于，剖析可能导致胆管细胞（胆管树内的细胞）恶性转化为胆管癌的机制，最终有望提供对胆管癌病因的了解，并增加胆管癌发展的机会。治疗这种致命癌症的新治疗方案。

项目成果

Orphan G protein receptor GPR55 as an emerging target in cancer therapy and management.

• DOI: 10.2147/cmar.s35175
• 发表时间: 2013
• 期刊: Cancer management and research
• 影响因子: 3.3
• 作者: Leyva-Illades D;Demorrow S
• 通讯作者: Demorrow S

Cholangiocarcinoma pathogenesis: Role of the tumor microenvironment.

• 发表时间: 2012
• 期刊: Translational gastrointestinal cancer
• 作者: D. Leyva-Illades;Matthew McMillin;M. Quinn;S. DeMorrow

Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events.

• DOI: 10.1038/labinvest.2012.110
• 发表时间: 2012-10
• 期刊: Laboratory investigation; a journal of technical methods and pathology

Recent advances in the understanding of the role of the endocannabinoid system in liver diseases.

• DOI: 10.1016/j.dld.2010.08.010
• 发表时间: 2011-03
• 期刊: DIGESTIVE AND LIVER DISEASE
• 影响因子: 4.5
• 作者: Huang, Li;Quinn, Matthew A.;Frampton, Gabriel A.;Golden, Lessie Eric;DeMorrow, Sharon
• 通讯作者: DeMorrow, Sharon

Progranulin: a novel regulator of gastrointestinal cancer progression.

• DOI: 10.3978/j.issn.2224-4778.2013.02.02
• 发表时间: 2013-07
• 期刊: Translational gastrointestinal cancer
• 作者: Demorrow S