Neurotensin in Fibrolamellar Liver Cancer

神经降压素在纤维板层肝癌中的作用

• 批准号: 9316571
• 负责人: KIMBERLY J RIEHLE
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316571
• 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; G-substrate; GRK1 gene; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic Transcription; Genomics; Goals; Growth Factor; Heat shock proteins; Hepatocyte; Histologic; Holoenzymes; Hormones; Human; Incidence; Individual; Light; Link; Liver; Liver Cirrhosis; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Mutation; Neurosecretory Systems; Neurotensin; Outcome Study; PRKACA gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Promoter Regions; Proprotein Convertases; Proteins; Reporting; Risk Factors; Role; Sampling; Secondary to; Signal Transduction; Signaling Protein; Systemic Therapy; Therapeutic; Transcript; Tumorigenicity; Up-Regulation; Variant; advanced disease; age group; autocrine; base; carcinogenesis; cell type; combat; desensitization; effective therapy; experimental study; fusion gene; insight; liver cell proliferation; liver development; liver injury; migration; molecular phenotype; mutant; novel therapeutics; overexpression; prohormone; receptor; targeted cancer therapy; targeted treatment; tumorigenesis; tumorigenic; young adult

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.

项目概要/摘要 纤维板层肝细胞癌 (FL-HCC) 是原发性肝癌的一种形式， 无潜在肝病的健康儿童和年轻人；大约 90% 的 HCC 这个年龄组是 FL-HCC。 HCC 作为一个整体是一种从组织学和病理学角度来看非常多样化的疾病。 从分子角度来看，绝大多数成人病例是在慢性肝损伤的情况下发生的 和肝硬化。相反，FL-HCC 显示一致的临床行为并具有同质性 组织学表现，但没有已知的危险因素。 FL-HCC 也不同于其他亚型 HCC 的原因在于它出现在正常肝脏中，并且由于这些患者在基线时是健康的，因此他们倾向于 患有晚期疾病，没有治愈的选择。目前尚无有效的非 FL-HCC 患者的手术治疗。因此，我们的目标是开发针对 FL-的靶向疗法 HCC患者通过详细了解这种疾病的分子发病机制。 最近，报道了 FL-HCC 的假定致病突变，并导致嵌合体 由编码热休克蛋白的基因的启动子区域和第一个外显子组成的转录本 (DNAJB1) 与编码蛋白质催化亚基的基因的大部分序列融合 激酶 A (PRKACA)。所得融合蛋白驱动致癌的机制 尽管我们最近证明 FL-HCC 中 PKA 活性增加，但仍然未知 与正常肝脏相比。目前的提案概述了将进一步研究的实验 FL-HCC 中 PKA 信号过多的驱动因素，重点关注神经内分泌激素在 这种病。具体来说，我们将 1) 评估神经降压素对发育的贡献 FL-HCC，2) 研究 DNAJB1-PRKACA 融合如何导致这些细胞中的神经内分泌激活 癌症，3) 定义神经降压素/PKA 信号在肝脏中的肿瘤学作用。总之， 我们建议研究 DNAJB1-PRKACA 蛋白产物的机制 与神经降压素协同作用，驱动 FL-HCC 致癌，为发展铺平道路 针对这种癌症的靶向治疗。