Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA.
The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
Sci Rep. 2021 Feb 11;11(1):3646. doi: 10.1038/s41598-021-82252-x.
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.
雄激素受体 (AR) 信号在肝细胞癌发生中的促进作用正在显现。在临床前模型中，包括二乙基亚硝胺 (DEN) 诱导的肝细胞癌 (HCC)，抗雄激素治疗可延缓肝癌发生。然而，晚期 HCC 患者的药物抗雄激素治疗失败，表明 AR 在 HCC 发病中起作用。本研究旨在描述 AR 在 DEN 诱导的肝炎症和癌变过程中的表达和功能，并评估预防性 AR 拮抗预防肝癌发生的疗效。我们证明，用恩扎卢胺进行药物 AR 拮抗可抑制肝细胞癌的发生。用恩扎卢胺治疗时，我们观察到 CYP2E1 表达减少，从而减少 DEN 诱导的肝细胞死亡和 DNA 乙基加合物。AR 蛋白表达分析表明，DEN 导致门脉成纤维细胞和白细胞中 AR 的初始上调，但不包括肝细胞，这表明肝细胞自主的 AR 信号传导对于 DEN 诱导的癌变不是必需的。通过手术去势消除雄激素信号可减少前致癌物库普弗细胞群，但不会改变 DEN 介导的免疫细胞募集或 AR 表达。在这项研究中，我们确定了抗雄激素干预可调节诱变 DNA 加合物、肿瘤起始和免疫细胞组成。此外，我们发现 AR 在 DEN 介导的癌变过程中既不存在于肝细胞中，也不是必需的。
