Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Pathology, University of Utah, Salt Lake City, Utah.
Gastroenterology. 2019 May;156(6):1788-1804.e13. doi: 10.1053/j.gastro.2019.01.010. Epub 2019 Jan 12.
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.
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.
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.
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.
The accession number in the Gene Expression Omnibus is GSE92544.
肝硬化患者患肝细胞癌（HCC）的风险很高，且其血清中雌激素水平常常升高。但雌激素如何促进肝生长仍不清楚。我们研究了雌激素在斑马鱼发育、肝再生和癌变过程中对肝细胞增殖的影响。我们还研究了人类肝细胞和肝组织。
在幼虫和成年阶段，通过选择性雌激素信号转导调节剂暴露斑马鱼。通过基因表达、荧光成像和组织学分析评估肝生长。我们监测了肝切除后的肝再生和化学致癌剂（二甲基苯并蒽）给药后的 HCC 发展。在共培养系统中测量人肝细胞的增殖。通过免疫组织化学测量 68 例患者 HCC 和非肿瘤肝组织中的 G 蛋白偶联雌激素受体（GPER1）水平。
暴露于 17β-雌二醇（E2）增加了幼虫和成年斑马鱼的肝细胞增殖和肝体积和质量。化学遗传和上位性实验表明，GPER1 通过磷脂酰肌醇 3-激酶蛋白激酶 B-雷帕霉素靶蛋白途径介导 E2 的作用：gper1 敲除和 mtor 敲除斑马鱼不会因 E2 而增加肝生长。与非肿瘤组织样本相比，患者 HCC 样本中 GPER1 水平升高；雌激素促进人原代肝细胞增殖。雌激素特异性地加速了雄性斑马鱼的肝癌发生。GPER1 的化学抑制或基因缺失显著减少了斑马鱼的肿瘤发生。
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，可调节发育、再生和肿瘤发生过程中的肝生长。GPER1 的抑制剂可能被开发用于肝癌的预防或治疗。
基因表达综合数据库中的注册号为 GSE92544。
