Chaturantabut, S., Shwartz, A., Evason, K.J., Cox, A.G., Labella, K., Schepers, A.G., Yang, S., Aravena, M., Houvras, Y., Mancio-Silva, L., Romano, S., Gorelick, D.A., Cohen, D.E., Zon, L.I., Bhatia, S.N., North, T.E., Goessling, W. (2019) 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. Gastroenterology. 156(6):1788-1804.e13.
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 co-culture system. We measured levels of G protein-coupled estrogen receptor (GPER1) in HCC and non-tumor liver tissues from 68 patients by immunohistochemistry.
Results Exposure to 17 beta-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 PI3K-Akt-mTOR 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 non-tumor tissues; 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.