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Estrogen Activation of G-Protein-Coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes.
雌激素激活 g蛋白偶联雌激素受体 1 调节磷酸肌醇 3-激酶和 mTOR 信号,以促进斑马鱼肝脏生长和人肝细胞增殖。
Hepatocarcinogenesis Sex Hormone Signal Transduction Transcription Regulation
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摘要

BACKGROUND & AIMS:Patients with cirrhosis are at high risk for hepatocellular carcinoma (HCC) and often have increased serum levels of estrogen. It is not clear how estrogen promotes hepatic growth. We investigated the effects of estrogen on hepatocyte proliferation during zebrafish development, liver regeneration, and carcinogenesis. We also studied human hepatocytes and liver tissues.
METHODS:Zebrafish were exposed to selective modifiers of estrogen signaling at larval and adult stages. Liver growth was assessed by gene expression, fluorescent imaging, and histologic analyses. We monitored liver regeneration after hepatocyte ablation and HCC development after administration of chemical carcinogens (dimethylbenzanthrazene). Proliferation of human hepatocytes was measured in a coculture system. We measured levels of G-protein-coupled estrogen receptor (GPER1) in HCC and nontumor liver tissues from 68 patients by immunohistochemistry.
RESULTS:Exposure to 17β-estradiol (E2) increased proliferation of hepatocytes and liver volume and mass in larval and adult zebrafish. Chemical genetic and epistasis experiments showed that GPER1 mediates the effects of E2 via the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin pathway: gper1-knockout and mtor-knockout zebrafish did not increase liver growth in response to E2. HCC samples from patients had increased levels of GPER1 compared with nontumor tissue samples; estrogen promoted proliferation of human primary hepatocytes. Estrogen accelerated hepatocarcinogenesis specifically in male zebrafish. Chemical inhibition or genetic loss of GPER1 significantly reduced tumor development in the zebrafish.
CONCLUSIONS:In an analysis of zebrafish and human liver cells and tissues, we found GPER1 to be a hepatic estrogen sensor that regulates liver growth during development, regeneration, and tumorigenesis. Inhibitors of GPER1 might be developed for liver cancer prevention or treatment.
TRANSCRIPT PROFILING:The accession number in the Gene Expression Omnibus is GSE92544.

译文

背景与目的: 肝硬化患者患肝细胞癌 (HCC) 的风险很高,并且通常血清雌激素水平升高。雌激素如何促进肝脏生长尚不清楚。我们研究了雌激素对斑马鱼发育、肝再生和癌变过程中肝细胞增殖的影响。我们还研究了人肝细胞和肝组织。
方法: 斑马鱼在幼虫和成虫阶段暴露于雌激素信号的选择性调节剂。通过基因表达、荧光成像和组织学分析评估肝脏生长。我们监测了肝细胞消融后的肝再生和给予化学致癌物 (二甲基苯并三嗪) 后的肝癌发展。在共培养系统中测量人肝细胞的增殖。我们通过免疫组织化学检测了 68 例患者的肝癌和非肿瘤肝组织中 g蛋白偶联雌激素受体 (GPER1) 的水平。
结果: 暴露于 17 β-雌二醇 (E2) 可增加幼虫和成虫斑马鱼的肝细胞增殖和肝脏体积及质量。化学遗传和上位实验表明,GPER1 通过磷酸肌醇 3-激酶-蛋白激酶 B-雷帕霉素途径的机制靶点介导 E2 的作用: gper1-knockout 和 mtor 敲除的斑马鱼对 e2 没有增加肝脏生长。与非肿瘤组织样本相比,来自患者的肝癌样本的 GPER1 水平增加; 雌激素促进人原代肝细胞的增殖。雌激素加速雄性斑马鱼的肝癌发生。GPER1 的化学抑制或遗传缺失显著降低了斑马鱼的肿瘤发展。
结论: 在对斑马鱼和人类肝细胞和组织的分析中,我们发现 GPER1 是一种肝雌激素传感器,在发育、再生和肿瘤发生过程中调节肝脏生长。GPER1 抑制剂可能被开发用于肝癌预防或治疗。
转录谱: 基因表达综合中的登录号是 gse92544。

Phosphoinositide 3-kinase

内分泌 细胞因子 临床研究术语
概述  :  

磷酸肌醇3-激酶(PI3K),是一类涉及细胞功能的酶,例如细胞生长,增殖,分化,运动,存活和细胞内运输,而这些细胞又参与癌症。PI3K能够使磷脂酰肌醇(PtdIns)的肌醇环的3位羟基磷酸化。该通路与癌基因PIK3CA和肿瘤抑制物PTEN一起,与癌症对胰岛素和IGF1的敏感性以及卡路里限制有关。 分类 ①I类PI3K 在体内催化磷脂酰肌醇(4,5)-双磷酸(PI(4,5)P 2)转化为磷脂酰肌醇(3,4,5)-三磷酸(PI(3,4,5)P 3

phosphoinositide   英/,fɔsfəui'nəusitaid/

释    义   n. 磷酸肌醇

例    句   The milestone for a central role of lipids in signal transduction was manifested by the discovery of the phosphoinositide cycle.磷酸肌醇循环的发现以里程碑的形式证明了脂质在细胞信号转导过程中发挥重要作用。

 

kinase   英 /ˈkaɪneɪz/   美 /ˈkɪnneɪz/

释    义   n. [生化] 激酶;致活酶

例    句   The scientists successfully identified the small enzyme molecule responsible, a gene called focal adhesion kinase.科学家成功分离出这种小小的酶分子,基因学上称之为局部粘着激酶。

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