G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis.
G protein-coupled estrogen receptor (GPER) is a novel estrogen-binding receptor involved in many pathological conditions, including cancer. In this study, we investigated the effect of GPER on hepatocellular carcinoma (HCC). Our data show GPER knockout in a diethylnitrosamine (DEN)-induced mouse tumor model significantly accelerated liver tumorigenesis, accompanied by enhanced immune cell infiltration, fibrosis, and the production of inflammatory factors, such as interleukin-6 (IL-6). We further delineated the function of GPER in macrophages and hepatic stellate cells (HSCs). Treatment with the selective GPER agonist, G-1, decreased the expression of IL-6 in bone marrow-derived macrophages, which was abrogated upon deficiency of GPER. In a HSC line (LX2), G-1 treatment downregulated the expression of α-smooth muscle actin. In addition, both GPER mRNA and protein levels were significantly lower in HCC compared with matched non-tumor tissues. However, modulating GPER expression did not affect the viability and proliferation of hepatoma cells in vitro. Together our results indicate that GPER protects against HCC tumorigenesis through regulating inflammatory responses rather than directly acting on tumor cells. Therefore, GPER activation may be a potential strategy for prevention and treatment of HCC.
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Tao
T
Wei
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Wei
W
Chen
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Liang
L
Wen
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Jian
J
Zhang
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Qi
Q
Zhang
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Jiaqi
J
Yang
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Hao
H
Liu
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Bryan Wei
BW
Chen
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Yue
Y
Zhou
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
Xinhua
X
Feng
Center for Immunology & Microbial Disease, Albany Medical College, Albany, NY, USA.
Qi
Q
Yang
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China. Electronic address: shirleybai57@hotmail.com.
Xueli
X
Bai
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China; Collaborative Innovation Center for Cancer Medicine, Zhejiang University, Guangzhou, China. Electronic address: liangtingbo@zju.edu.cn.
Tingbo
T
Liang
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004052:Diethylnitrosamine; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011960:Receptors, Estrogen / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
C109584:GPER1 protein, human; C532507:GPER1 protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C577686:interleukin-6, mouse; D004052:Diethylnitrosamine
GPER; Hepatocellular carcinoma; Inflammation; Interleukin-6