[논문]Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin

Lee, Sang R.; Jeong, Su Hee; Heo, Jun H.; Jo, Seong Lae; Ko, Je-Won; Kwun, Hyo-Jung; Hong, Eui-Ju

doi:10.3390/ijms222212557

[해외논문] Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin 원문보기

International journal of molecular sciences, v.22 no.22, 2021년, pp.12557 -

Lee, Sang R. , Jeong, Su Hee , Heo, Jun H. , Jo, Seong Lae , Ko, Je-Won , Kwun, Hyo-Jung , Hong, Eui-Ju

Abstract ▼ AI-Helper

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.

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