Neurotensin in Fibrolamellar Liver Cancer

项目总结/摘要 纤维板层型肝细胞癌（FL-HCC）是原发性肝癌的一种形式， 健康的儿童和年轻人没有潜在的肝脏疾病;大约90%的HCC， 这个年龄组是FL-HCC。HCC作为一个整体是一种非常不同的疾病，从组织学和 从分子的角度来看，在绝大多数成人病例中， 和肝硬化。相反，FL-HCC显示出一致的临床行为，并且具有同质性。 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的原因在于它发生在正常肝脏中，并且由于这些患者在基线时是健康的，他们倾向于 目前病情严重，没有治愈的方法目前没有有效的非- FL-HCC患者的外科治疗。因此，我们的目标是开发FL的靶向治疗- 通过对HCC患者详细了解本病的分子发病机制。 最近，据报道，在FL-HCC中存在一种推定的致病突变，并导致嵌合的 由编码热休克蛋白的基因的启动子区和第一外显子组成的转录物 （DNAJB 1）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）。由此产生的融合蛋白驱动致癌作用的机制 尽管我们最近证实FL-HCC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中过量PKA信号传导的驱动因素，重点关注神经内分泌激素在 这种疾病。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DNAJB 1-PRKACA融合如何导致这些细胞中的神经内分泌激活， 癌症，和3）定义肝中神经降压素/PKA信号传导的肿瘤学作用。总的来说， 我们建议研究DNAJB 1-PRKACA蛋白产物 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。

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.