Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression

Abstract

Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.

Sexual Dimorphism in Chronic Hepatitis B Virus (HBV) Infection: Evidence to Inform Elimination Efforts

“…In a transgenic mouse model, HNF4-α increases HBV transcription by binding the enhancer I (EnhI) region of the HBV genome 87 . Deletion of ER-α in female mice removes the protective influence of oestrogen against hepatocarcinogenesis; relative to wild-type these knock-out animals had a nine-fold increased risk of tumorigenesis on exposure to carcinogens 88 . In cell culture experiments, estradiol reduces expression of the hepatocyte surface protein NTCP (sodium taurocholate co-transporting polypeptide), the main entry receptor for HBV 89,90 , which is another possible mechanism for protection in females 19 .…”

Therapeutic Value of Estrogen Receptor α in Hepatocellular Carcinoma Based on Molecular Mechanisms

“…ERα is considered to regulate inflammation, iron homoeostasis, energy metabolism and other processes to protect the liver. 9 – 12 Moreover, a multitude of studies have shown that the expression of ERα in primary HCC tissues is decreased compared to normal liver tissues or the adjacent tissues, which indirectly confirmed the suppressive effects of ERα in HCC. 13 – 15 In light of this anti-tumor effect of ERα in HCC, reactivating ERα signaling can offer a new therapeutic strategy in HCC prevention and treatment.…”

Targeting Acid Ceramidase Ameliorates Fibrosis in Mouse Models of Nonalcoholic Steatohepatitis

“…Human NASH studies as well as studies on hepatocellular carcinoma (HCC) incidence have demonstrated a significant difference in incidence between males and females. Studies have illustrated a clear link between estrogen and the decreased occurrence of HCC 32,33 . The same phenomenon holds true for NASH.…”