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

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 infl...

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Autores principales:	Sang R. Lee, Su Hee Jeong, Jun H. Heo, Seong Lae Jo, Je-Won Ko, Hyo-Jung Kwun, Eui-Ju Hong
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	17α-ethinylestradiol SHBG HCC liver cancer EE2 androgen Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/aa028bec0f91437980d2cbfdf1b58801
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spelling	oai:doaj.org-article:aa028bec0f91437980d2cbfdf1b588012021-11-25T17:57:48ZDietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin10.3390/ijms2222125571422-00671661-6596https://doaj.org/article/aa028bec0f91437980d2cbfdf1b588012021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12557https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Hepatocellular 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.Sang R. LeeSu Hee JeongJun H. HeoSeong Lae JoJe-Won KoHyo-Jung KwunEui-Ju HongMDPI AGarticle17α-ethinylestradiolSHBGHCCliver cancerEE2androgenBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12557, p 12557 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	17α-ethinylestradiol SHBG HCC liver cancer EE2 androgen Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	17α-ethinylestradiol SHBG HCC liver cancer EE2 androgen Biology (General) QH301-705.5 Chemistry QD1-999 Sang R. Lee Su Hee Jeong Jun H. Heo Seong Lae Jo Je-Won Ko Hyo-Jung Kwun Eui-Ju Hong Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin
description	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.
format	article
author	Sang R. Lee Su Hee Jeong Jun H. Heo Seong Lae Jo Je-Won Ko Hyo-Jung Kwun Eui-Ju Hong
author_facet	Sang R. Lee Su Hee Jeong Jun H. Heo Seong Lae Jo Je-Won Ko Hyo-Jung Kwun Eui-Ju Hong
author_sort	Sang R. Lee
title	Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin
title_short	Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin
title_full	Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin
title_fullStr	Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin
title_full_unstemmed	Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin
title_sort	dietary intake of 17α-ethinylestradiol promotes hcc progression in humanized male mice expressing sex hormone-binding globulin
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/aa028bec0f91437980d2cbfdf1b58801
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Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin

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