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Page 8 of 12 Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89

Naugler et al. [54] In mice administered with IL-6 A higher HCC incidence was Higher induction of IL-6
DEN, HCC incidence, and observed in male vs. female DEN- in Kupffer cells under liver
its relationship with hepatic induced hepatocarcinogenesis injury partly explains higher
IL-6 induction, Toll-like model. The higher incidence of incidence of HCC in males
receptor adaptor protein HCC in males was associated while estrogens protect
MyD88, and oestrogen with higher MyD88-dependent females from HCC, in part,
were evaluated in male and induction of IL-6 in male hepatic via reducing IL-6
female mice Kupffer cells under liver injury.
Estradiol inhibited IL-6 production
by hepatic Kupffer cells
Fibrosis
Yasuda et al. [55] Using the DEN model, Stellate cell In male rats the induction of Higher oestrogen protects
hepatic fibrosis was activation/ fibrotic response was significantly premenopausal women
compared between male fibrogenesis stronger than in female rats. from advanced hepatic
and female rats Estradiol reduced hepatic fibrosis, a major risk factor
fibrogenesis in male rats while of HCC
concomitant administration of a
neutralizing antibody against rat
estradiol enhanced fibrogenesis.
Oophorectomy in the female rats
had a fibrogenic effect
Tumor suppressor genes
Xie et al. [56] The mechanistic link Bile acid/ STZ-HFD feeding induced a Sex differences in
between microbiota microbiota higher incidence of HCC in male microbiota lead to
and hepatocellular mice, which was associated with higher intrahepatic
carcinogenesis using a increased intrahepatic retention of retention of hydrophobic
STZ-HFD induced NASH- hydrophobic BAs and decreased BAs, decreased tumor
HCC murine model and hepatic expression of tumor- suppressor microRNA in
compared results for both suppressive microRNAs. the liver, and an increased
sexes Metagenomic analysis showed incidence of HCC in male
differences in gut microbiota mice
involved in BA metabolism
between male and female mice.
Treating STZ-HFD male mice
with 2% cholestyramine led to
significant improvement of hepatic
BA retention, tumor-suppressive
microRNA expressions, microbial
gut communities, and prevention
of HCC
ALS: alkali labile sites; AMPK: AMP-activated protein kinase; BA: bile acids; CT: computed tomography; DEN: diethylnitrosamine; FFA:
free fatty acids; FPG: DNA repair glycosylase; IL-6: Interleukin-6; NASH-HCC: nonalcoholic steatohepatitis-hepatocellular carcinoma;
SSB: single strand breaks; SD: sprague dawley; STZ-HFD: streptozotocin-high fat diet

significantly varies in the literature, probably due to the differences in the methodologies and populations
[64]
of the studies (e.g., ethnicity, sex), as well as stage and aetiologies of disease . HCC tumour tissues express
both oestrogen receptor alpha (ERα) and beta (ERβ), and also a variant form of ERα (vERα), which lacks
exon 5 in the hormone-binding domain . Compared to patients with ER-negative HCC, patients with
[65]
[66]
ER-positive HCC have a shorter survival rate after curative resection . Several randomized controlled
trials were conducted to ascertain whether blockage of oestrogen signalling in HCC by the anti-oestrogen
tamoxifen would improve the survival of patients with HCC. However, the results were consistently
negative [67,68] . The presence of the liver vER receptor in the tumour is a strong negative predictor of survival
in inoperable HCC patients and is a marker of clinical aggressiveness compared to wild-type ERαn [69,70] .
HCC positive for the vER receptor is unresponsive to tamoxifen but responds to megestrol .
[71]
Sex differences in HCC biology have extensively been explored in recent years in functional signatures of
[73]
[73]
differentially expressed genes [71,72] , expression quantitative trait loci (eQTL) , and cancer-driver genes .
These studies strongly suggest that HCC in males and females are biologically distinct and may respond
differently to treatments. This is in agreement with epidemiological data summarized in Table 1. However,
no randomized controlled trials have demonstrated sex differences in HCC treatment response or clinical
outcomes. The consideration of sex and women’s reproductive history in clinical studies designs and