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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.

项目总结/文摘