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Gastroenterology. 2019 May;156(6):1788-1804.e13. doi: 10.1053/j.gastro.2019.01.010. Epub 2019 Jan 12.

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.

Author information

1
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
2
Department of Pathology, University of Utah, Salt Lake City, Utah.
3
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
4
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
5
Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
6
Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York.
7
Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.
8
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
9
Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland; Harvard Stem Cell Institute, Cambridge, Massachusetts; Dana-Farber Cancer Institute, Boston, Massachusetts.
10
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
11
Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts.
12
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts; Dana-Farber Cancer Institute, Boston, Massachusetts; Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Divison of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: wolfram_goessling@hms.harvard.edu.

Abstract

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.

KEYWORDS:

Hepatocarcinogenesis; Sex Hormone; Signal Transduction; Transcription Regulation

PMID:
30641053
PMCID:
PMC6532055
[Available on 2020-05-01]
DOI:
10.1053/j.gastro.2019.01.010
[Indexed for MEDLINE]

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