Serotonergic antidepressants as liver tumor preventives

项目摘要/摘要 由于日益增长的肥胖，美国人患肝细胞癌的风险正在增加 流行病及其与脂肪肝、脂肪性肝炎和肝硬变的关系。目前还没有药物治疗 显示可预防慢性肝病高危患者的肝细胞癌。长期目标是定义 肝癌发生机制，为改进预防、诊断工具和 肝细胞癌的治疗。该提案的总体目标是通过以下方式确定细胞和分子机制 哪种5-羟色胺促进和抑制肝脏生长和肿瘤形成。中心假说 这一建议的核心是：1)5-羟色胺通过刺激5-羟色胺促进肝脏生长和肿瘤的发生 2)5-羟色胺能抗抑郁药通过以下途径抑制肝脏生长和肿瘤的发生 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脏生长中的细胞和分子作用；2)确定 阿米替林通过HTR2A抑制肝脏生长和肿瘤形成；3)识别下游基因 阿米替林对-连环蛋白驱动的肝生长和肿瘤发生的影响 阿米替林的作用需要激活-连环蛋白。在目标1中，HTR2A介导5-羟色胺的假设 将通过检测HTR2A基因敲除对肝癌细胞生长的影响来测试对肝癌细胞的生长促进作用 人肝癌细胞系的5-羟色胺反应性。同时，HTR2A同源基因将被拆除 在斑马鱼肝癌模型中确定介导5-羟色胺促生长的受体和细胞类型(S) 对活体肝细胞的影响。在目标2中，阿米替林抑制肝脏生长和肿瘤的假说 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 和斑马鱼一样。在目标3中，一个优先的基因列表，被阿米替林治疗下调 小鼠肝癌的特征是对肝脏生长和肿瘤发生的影响以及对阿米替林的反应 使用斑马鱼和小鼠肝细胞癌模型。阿米替林作用需要激活-连锁素的假说 将会受到考验。我们期望拟议的研究能够确定5-羟色胺信号和5-羟色胺能 抗抑郁药调节肝脏生长和肿瘤形成。这项研究具有重要意义，因为它将形成 为高危患者确定预防肝癌的药物的基础，这可能会挽救数千人的生命 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.