Serotonergic antidepressants as liver tumor preventives

项目总结/摘要 由于肥胖的增加，美国人患肝细胞癌（HCC）的风险正在增加 流行病及其与脂肪肝、脂肪性肝炎和肝硬化的关系。没有任何药物 在患有慢性肝病的高危患者中预防HCC。长期目标是确定 肝癌发生机制，为改进预防，诊断工具和 治疗HCC。该提案的总体目标是通过以下方式确定细胞和分子机制： 血清素促进肝脏生长，抗抑郁药抑制肝脏生长和肿瘤形成。核心假设 1）血清素通过刺激血清素促进肝脏生长和肿瘤发生， 受体HTR2A;和2）肾上腺素能抗抑郁药抑制肝生长和肿瘤发生， HTR2A的拮抗作用。提出了以下具体目标来检验这一假设：1）确定 HTR2A在促进肝肿瘤细胞活力和肝生长中的细胞和分子作用; 2）确定HTR2A是否 阿米替林通过HTR2A抑制肝脏生长和肿瘤形成; 3）鉴定下游基因， 介导阿米替林对β-连环蛋白驱动的肝脏生长和肿瘤发生的影响，并确定是否 阿米替林的作用需要活化的β-连环蛋白。在目的1中，HTR2A介导5-羟色胺的 对HCC细胞的生长促进作用将通过测量HTR2A敲低对HCC细胞的作用来测试。 人肝癌细胞系的5-羟色胺反应性。同时，HTR2A直系同源物将被敲除， 在斑马鱼HCC模型中，以确定介导5-羟色胺促生长的受体和细胞类型 对体内肝细胞的影响。在目的2中，阿米替林抑制肝脏生长和肿瘤的假设 通过抑制HTR2A的形成将在人肝癌细胞中使用互补方法进行测试 线和斑马鱼，如目标1中所述。在目标3中，列出了一个优先的基因列表，这些基因在阿米替林治疗中下调， 小鼠HCC，将表征其对肝生长和肿瘤发生的影响以及对阿米替林的反应 使用斑马鱼和小鼠HCC模型。阿米替林的作用需要激活β-连环蛋白的假说 会得到考验我们希望拟议中的研究能够确定血清素信号传导和多巴胺能神经递质是如何作用的。 抗抑郁药调节肝脏生长和肿瘤发生。这项研究意义重大，因为它将形成 为确定预防高危患者肝癌的药物奠定了基础，这可能挽救数千人的生命。 每年.

PROJECT SUMMARY/ABSTRACT The number of Americans at risk for hepatocellular carcinoma (HCC) is increasing due to the growing obesity epidemic and its association with fatty liver disease, steatohepatitis, and cirrhosis. No medications have been shown to prevent HCC in high-risk patients with chronic liver disease. The long-term goal is to define mechanisms of hepatocarcinogenesis, providing a foundation for improved preventives, diagnostic tools, and treatments for HCC. The overall objective of this proposal is to identify cellular and molecular mechanisms by which serotonin promotes and antidepressants inhibit liver growth and tumor formation. The central hypothesis of this proposal is that 1) serotonin promotes liver growth and tumorigenesis by stimulating the serotonin receptor HTR2A on hepatocytes; and 2) serotonergic antidepressants inhibit liver growth and tumorigenesis by antagonism of HTR2A. The following specific aims are proposed to test this hypothesis: 1) Determine the cellular and molecular role of HTR2A in promoting liver tumor cell viability and liver growth; 2) Determine if amitriptyline suppresses liver growth and tumor formation via HTR2A; 3) Identify downstream genes that mediate amitriptyline’s effects on -catenin-driven liver growth and tumorigenesis and determine whether amitriptyline’s effects required activated -catenin. In Aim 1, the hypothesis that HTR2A mediates serotonin’s growth-promoting effects on HCC cells will be tested by measuring the effect of HTR2A knockdown on serotonin responsiveness of human liver cancer cell lines. In parallel, HTR2A orthologs will be knocked down in a zebrafish HCC model to determine the receptor and cell type(s) that mediate serotonin’s growth-promoting effects on hepatocytes in vivo. In Aim 2, the hypothesis that amitriptyline suppresses liver growth and tumor formation via inhibition of HTR2A will be tested using complementary approaches in human liver cancer cell lines and zebrafish as in Aim 1. In Aim 3, a prioritized list of genes, downregulated by amitriptyline treatment in mouse HCC, will be characterized for effects on liver growth and tumorigenesis and response to amitriptyline using zebrafish and mouse HCC models. The hypothesis that amitriptyline’s actions require activated -catenin will be tested. We expect the proposed studies to define how serotonin signaling and serotonergic antidepressants modulate liver growth and tumorigenesis. This research is significant because it will form the basis for identifying drugs to prevent liver cancer in high-risk patients, which could save thousands of lives each year.