Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

Abstract

The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro , in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

“…43 However, the transition of IHCA into HCC and thus tumor initiation is not frequently found. 47 In the present study, we observed a reduction in the DENinduced HCC load in gp130…”

Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

“…This protective role of E2 in the gender disparity in hepatocarcinogenesis is recognized in recent years, and several investigations have attempted to address the importance of E2 in the pathogenesis of HCC. [3][4][5]8 Naugler et al 5 showed that E2 inhibited the release of IL-6 from Kupffer's cells, which further reduced the risk of cancer in female mice in diethylnitrosamine-induced hepatic carcinogenesis. Subsequently, Yang et al 21 showed that E2 suppressed hepatic tumor growth via regulating the polarization of infiltrating macrophages.…”

“…2 The remarkable gender disparity observed in the incidence of HCC suggests that the sex steroid hormone estrogen may elicit a protective effect against this disease. [3][4][5] The biological functions of 17β-estradiol (E2), a major form of estrogen, are mainly mediated by its two specific estrogen receptors, ERα and ERβ. The role of ERα in carcinogenesis has been widely investigated and elucidated, whereas ERβ was first identified in 1996 (ref.…”

Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B #

“…Lower estrogen activity, either caused by menopause or oophorectomy, is a risk factor for female HCC. 25 We recently showed decreased estrogen receptor-␣ protein in many female HCCs, 26 which could be caused by a mechanism regulated by microRNA-18a. 27 Moreover, Naugler et al demonstrated that estrogens could protect hepatocytes from malignant transformation via down-regulation of interleukin-6 secretion from Kupffer cells.…”