Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks

Abstract A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen...

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Autores principales:	Timothy H. Helms, Riley D. Mullins, Jennifer M. Thomas-Ahner, Samuel K. Kulp, Moray J. Campbell, Fabienne Lucas, Nathan Schmidt, Dana M. LeMoine, Surafel Getaneh, Zhiliang Xie, Mitch A. Phelps, Steven K. Clinton, Christopher C. Coss
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c25b0208e10b4d27952527a2f7974c56
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spelling	oai:doaj.org-article:c25b0208e10b4d27952527a2f7974c562021-12-02T14:26:54ZInhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks10.1038/s41598-021-82252-x2045-2322https://doaj.org/article/c25b0208e10b4d27952527a2f7974c562021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82252-xhttps://doaj.org/toc/2045-2322Abstract A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen therapy in advanced HCC patients fails, suggesting that AR plays a role in HCC onset. This study aims to characterize AR expression and function throughout DEN-induced liver inflammation and carcinogenesis and evaluate the efficacy of prophylactic AR antagonism to prevent hepatocarcinogenesis. We demonstrate that pharmacologic AR antagonism with enzalutamide inhibits hepatocellular carcinogenesis. With enzalutamide treatment, we observe decreased CYP2E1 expression, reducing DEN-induced hepatocyte death and DNA ethyl-adducts. AR protein expression analyses show that DEN causes an initial upregulation of AR in portal fibroblasts and leukocytes, but not hepatocytes, suggesting that hepatocyte-autonomous AR signaling is not essential for DEN-induced carcinogenesis. Ablating androgen signaling by surgical castration reduced pre-carcinogen Kupffer cell populations but did not alter DEN-mediated immune cell recruitment nor AR expression. In this study, we identified that anti-androgen interventions modulate mutagenic DNA adducts, tumour initiation, and immune cell composition. Additionally, we find that AR expression in hepatocytes is not present during nor required for early DEN-mediated carcinogenesis.Timothy H. HelmsRiley D. MullinsJennifer M. Thomas-AhnerSamuel K. KulpMoray J. CampbellFabienne LucasNathan SchmidtDana M. LeMoineSurafel GetanehZhiliang XieMitch A. PhelpsSteven K. ClintonChristopher C. CossNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Timothy H. Helms Riley D. Mullins Jennifer M. Thomas-Ahner Samuel K. Kulp Moray J. Campbell Fabienne Lucas Nathan Schmidt Dana M. LeMoine Surafel Getaneh Zhiliang Xie Mitch A. Phelps Steven K. Clinton Christopher C. Coss Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks
description	Abstract A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen therapy in advanced HCC patients fails, suggesting that AR plays a role in HCC onset. This study aims to characterize AR expression and function throughout DEN-induced liver inflammation and carcinogenesis and evaluate the efficacy of prophylactic AR antagonism to prevent hepatocarcinogenesis. We demonstrate that pharmacologic AR antagonism with enzalutamide inhibits hepatocellular carcinogenesis. With enzalutamide treatment, we observe decreased CYP2E1 expression, reducing DEN-induced hepatocyte death and DNA ethyl-adducts. AR protein expression analyses show that DEN causes an initial upregulation of AR in portal fibroblasts and leukocytes, but not hepatocytes, suggesting that hepatocyte-autonomous AR signaling is not essential for DEN-induced carcinogenesis. Ablating androgen signaling by surgical castration reduced pre-carcinogen Kupffer cell populations but did not alter DEN-mediated immune cell recruitment nor AR expression. In this study, we identified that anti-androgen interventions modulate mutagenic DNA adducts, tumour initiation, and immune cell composition. Additionally, we find that AR expression in hepatocytes is not present during nor required for early DEN-mediated carcinogenesis.
format	article
author	Timothy H. Helms Riley D. Mullins Jennifer M. Thomas-Ahner Samuel K. Kulp Moray J. Campbell Fabienne Lucas Nathan Schmidt Dana M. LeMoine Surafel Getaneh Zhiliang Xie Mitch A. Phelps Steven K. Clinton Christopher C. Coss
author_facet	Timothy H. Helms Riley D. Mullins Jennifer M. Thomas-Ahner Samuel K. Kulp Moray J. Campbell Fabienne Lucas Nathan Schmidt Dana M. LeMoine Surafel Getaneh Zhiliang Xie Mitch A. Phelps Steven K. Clinton Christopher C. Coss
author_sort	Timothy H. Helms
title	Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks
title_short	Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks
title_full	Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks
title_fullStr	Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks
title_full_unstemmed	Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks
title_sort	inhibition of androgen/ar signaling inhibits diethylnitrosamine (den) induced tumour initiation and remodels liver immune cell networks
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c25b0208e10b4d27952527a2f7974c56
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Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks

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