Neurotensin in Fibrolamellar Liver Cancer

神经降压素在纤维板层肝癌中的作用

基本信息

批准号：
9176932
负责人：
KIMBERLY J RIEHLE
金额：
$ 16.8万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176932
关键词：
Adult Affect Anchorage-Independent Growth Appearance Arrestins BAY 54-9085 Behavior Binding Biological Assay CREB1 gene Cancer Etiology Catalytic Domain Cell Culture Techniques Cell Line Cell Proliferation Cessation of life Child Chimeric Proteins Chromosomes, Human, Pair 19 Chronic Clinical Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA Sequence Alteration Data Development Diagnosis Disease Event Exons Fibrolamellar Hepatocellular Carcinoma G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GRK1 gene GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genes Genetic Transcription Genomics Goals Growth Heat shock proteins Hepatocyte Histologic Holoenzymes Hormones Human Incidence Individual Left Light Link Liver Liver Cirrhosis Liver diseases Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mediating Modeling Molecular Mutation Neurosecretory Systems Neurotensin Operative Surgical Procedures Outcome Study PRKACA gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphotransferases Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Process Promoter Regions Proprotein Convertases Proteins Reporting Risk Factors Role Sampling Secondary to Signal Transduction Systemic Therapy Therapeutic Transcript Up-Regulation Variant Work abstracting advanced disease age group autocrine base beta-arrestin carcinogenesis cell type combat desensitization effective therapy fusion gene insight liver cell proliferation liver injury migration molecular phenotype mutant novel therapeutics overexpression prohormone receptor research study targeted cancer therapy targeted treatment tumorigenesis tumorigenic young adult

项目摘要

Project Summary/Abstract Fibrolamellar hepatocellular carcinoma (FL-HCC) is a form of primary liver cancer that afflicts healthy children and young adults without underlying liver disease; approximately 90% of HCCs in this age group are FL-HCCs. HCC as a whole is a remarkably diverse disease from a histologic and molecular standpoint, and in the vast majority of adult cases arises in the setting of chronic liver injury and cirrhosis. Conversely, FL-HCCs display consistent clinical behavior and have a homogeneous histologic appearance, but there are no known risk factors. FL-HCC also differs from other subtypes of HCC in that it arises in normal liver, and since these patients are healthy at baseline, they tend to present with advanced disease, leaving no options for cure. Currently there are no effective non- surgical therapies for patients with FL-HCC. Therefore we aim to develop targeted therapies for FL- HCC patients through a detailed understanding of the molecular pathogenesis of this disease. Recently, a putative causative mutation in FL-HCC was reported, and results in a chimeric transcript consisting of the promoter region and first exon of a gene encoding a heat shock protein (DNAJB1) fused to the majority of the sequence for the gene encoding the catalytic subunit of protein kinase A (PRKACA). The mechanisms by which the resultant fusion protein drives carcinogenesis remain unknown, though we have recently demonstrated increased PKA activity in FL-HCCs compared to normal livers. The current proposal outlines experiments that will further investigate drivers of excess PKA signaling in FL-HCC, with focus on the role of a neuroendocrine hormone in this disease. Specifically, we will 1) evaluate the contribution of neurotensin to the development of FL-HCC, 2) investigate how the DNAJB1-PRKACA fusion leads to neuroendocrine activation in these cancers, and 3) define the oncologic effects of neurotensin/PKA signaling in the liver. In summary, we propose to investigate the mechanisms by which the DNAJB1-PRKACA protein product synergizes with neurotensin to drive carcinogenesis in FL-HCC, paving the way for the development of targeted therapies for this cancer.

项目摘要/摘要纤维状肝细胞癌（FL-HCC）是一种受苦的原发性肝癌的形式健康的儿童和年轻人，没有潜在的肝病；大约90％的HCC 这个年龄段是FL-HCC。整个HCC是从组织学和分子的角度，在绝大多数成年病例中，出现在慢性肝损伤的情况下和肝硬化。相反，FL-HCC表现出一致的临床行为，并且具有同质性组织学外观，但没有已知的危险因素。 FL-HCC也不同于其他亚型 HCC的肝脏是正常肝脏出现的，由于这些患者在基线时健康，因此他们倾向于出现晚期疾病，没有治愈的选择。目前没有有效的非 FL-HCC患者的手术疗法。因此，我们旨在开发针对FL-的目标疗法 HCC患者通过详细了解该疾病的分子发病机理。最近，报告了FL-HCC中推定的因果突变，并导致嵌合由启动子区域和编码热休克蛋白的基因的第一个外显子组成的成绩单（DNAJB1）与编码蛋白质催化亚基的基因的大多数融合激酶A（prkaca）。所得融合蛋白驱动致癌的机制仍然未知，尽管我们最近证明了FL-HCC的PKA活性增加与普通肝脏相比。当前的提案概述了将进一步调查的实验 FL-HCC中过量PKA信号的驱动因素，重点是神经内分泌激素在这种疾病。具体而言，我们将1）评估神经素对发展的贡献 FL-HCC，2）研究DNAJB1-PRKACA融合如何导致神经内分泌激活癌症和3）定义神经素/PKA信号在肝脏中的肿瘤学效应。总之，我们建议研究DNAJB1-PRKACA蛋白产物的机制与神经素协同促进FL-HCC的致癌作用，为发展铺平道路该癌症的靶向疗法。