Neurotensin in Fibrolamellar Liver Cancer

神经降压素在纤维板层肝癌中的作用

• 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
• 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

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 摘要纤维板层状肝细胞癌是一种常见的原发性肝癌。 没有潜在肝病的健康儿童和年轻人；大约90%的HC 这一年龄段为FL-HC。作为一个整体，肝细胞癌是一种非常多样化的疾病，与组织学和 分子观点，并且在绝大多数成人病例中发生在慢性肝损伤的背景下 和肝硬变。相反，FL-HC表现出一致的临床行为，并具有同质性 组织学表现，但尚无已知的危险因素。FL-HCC也不同于其他亚型 因为它发生在正常肝脏，而且由于这些患者在基线时是健康的，他们倾向于 患有晚期疾病，没有治愈的选择。目前还没有有效的非 肝细胞癌患者的外科治疗。因此，我们的目标是开发针对FL的靶向治疗方法。 通过对肝细胞癌患者的分子发病机制的详细了解。 最近，一种可能的FL-肝细胞癌致病突变被报道，并导致嵌合体 由热休克蛋白编码基因的启动子区域和第一外显子组成的转录本 (DNAJB1)与编码蛋白质催化亚基基因的大部分序列融合 蛋白激酶A(PRKACA)。所产生的融合蛋白驱动致癌的机制 仍不清楚，尽管我们最近发现FL-HC中PKA活性增加 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中过度PKA信号的驱动因素，重点关注神经内分泌激素在FL-HCC中的作用 这种病。具体地说，我们将1)评估神经降压素在糖尿病发展中的作用。 2)研究DNAJB1-PRKACA融合是如何导致这些细胞的神经内分泌激活的 3)定义肝脏中神经降压素/PKA信号的肿瘤学效应。总而言之， 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推动FL-HCC的癌变，为发展铺平道路 针对这种癌症的靶向治疗。