Abstract
Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences HCC risk in male androgenic environments, using mice expressing human sex hormone-binding globulin (SHBG). Two-week-old male mice were injected with diethyl-nitrosamine (DEN, 25 mg/kg) and fed an EE2 diet for 10 weeks from 30 weeks of age. Development and characteristics of liver cancer were evaluated in 40-week-old mice via molecular and histological analyses. Although EE2 did not increase HCC progression in wild-type mice, SHBG mice exhibited remarkably higher HCC risk when fed EE2. The livers of EE2-treated SHBG mice exhibited substantially increased pro-inflammatory necrosis with high plasma levels of ALT and HMGB1, and intrahepatic injury and fibers. Additionally, increased androgen response and androgen-mediated proliferation in the livers of EE2-treated SHBG mice and EE2-exposed hepatocytes under SHBG conditions were observed. As a competitor of SHBG-androgen binding, EE2 could bind with SHBG and increase the bioavailability of androgen. Our results revealed that EE2 is a novel risk factor in androgen-dominant men, predisposing them to HCC risk.
Highlights
As the female hormone 17β-estradiol (E2) is a potent suppressor of the hepatic proinflammatory response, which is essential for liver cancer progression, hepatocellular carcinoma (HCC) is considered a female-protective neoplasm [1]
Tumor foci were similar in WT EE2 livers and WT livers, they were substantially larger in Sex hormone-binding globulin (SHBG) EE2 livers than in SHBG livers
SHBG EE2 tumor showed a larger area of aggregated nuclei than other tumors (Figure 1G). These results indicate that EE2-induced HCC progression requires sex hormone regulation by SHBG in mice, suggesting that EE2 effects are accentuated or EE2 affects other sex hormone actions of SHBG
Summary
As the female hormone 17β-estradiol (E2) is a potent suppressor of the hepatic proinflammatory response, which is essential for liver cancer progression, hepatocellular carcinoma (HCC) is considered a female-protective neoplasm [1]. SHBG in the female reproductive organs suppresses estrogenic action [6], the post-menopausal estrogenic was accentuated by SHBG in a high-fat-fed liver [8], suggesting that hormonal regulation by SHBG is affected by physiological sex hormone concentrations. This indicates that the regulation of sex steroid hormones by SHBG is not coherent under all physiological conditions; SHBG can be regarded as a crucial sex steroid hormone modulator and could be involved in sex steroid hormone-related pathogenesis
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