Gender Disparity of Hepatocellular Carcinoma: The Roles of Sex Hormones

Abstract

Men have a higher incidence of hepatocellular carcinoma (HCC) than women. Epidemiologic and animal studies have suggested that it might be due to the stimulatory effects of androgen and the protective effects of estrogen. Recently, increasing molecular mechanisms underlying the carcinogenic effect of both sex hormones were reported. Knockout of androgen receptor (AR) expression in hepatocytes delayed the development of N′,N′-diethylnitrosamine (DEN)-induced HCC, suggesting the active AR pathway in augmenting the HCC risk. Moreover, an intriguing interaction between the viral protein of hepatitis B virus X protein (HBx) and the androgen pathway was established. HBx can enhance the transcriptional activity of AR in a ligand concentration-dependent manner, mainly through its effects on the c-Src and GSK-3β kinase pathways. The studies from the DEN-induced HCC mouse model further provided a mechanism for the protective role of estrogen in female HCC. Estrogen can protect hepatocytes from malignant transformation via downregulation of IL-6 release from Kupffer cells, a critical process in this mouse model. Intriguingly, suppression of the ERα protein by overexpression of miR-18a, which occurs preferentially in female HCC, was identified as a novel mechanism to block the tumor-protective function of estrogen in female HCC. In conclusion, the current studies demonstrated that the gender disparity of HCC is attributed by both androgen and estrogen sex hormone pathways, with distinct roles in each gender. Therefore, the ligand and the receptor factors of both sex hormones need to be included for assessing the relative risk of HCC patients of each gender.

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.…”

Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient

“…Interestingly, elevated levels of active androgens represent a well-described risk factor for HCC development, accounting for the higher incidence of HCC among males (43). Finally, the proteome also was enriched in immune response pathways, possibly indicative of inflammation in the tumor.…”

A potential explanation of the reported low prevalence of hepatitis B virus infection in patients with systemic lupus erythematosus

“…Incidental Wndings in each were that healthy volunteer HBV carriers had higher testosterone (T) concentrations than healthy uninfected volunteer controls (P = 0.045 and P = 0.0006, respectively, both two-way). The reason for this is not established and not directly relevant to the present note (though it may relate to variation in rates of viral replication in diVerent hormonal environments, if we may be guided by mouse models [4][5][6]). …”