Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells

// Hsueh-Chou Lai 1, 2 , Chun-Chieh Yeh 1, 2 , Long-Bin Jeng 1 , Shang-Fen Huang 2 , Pei-Ying Liao 2 , Fu-Ju Lei 1, 2 , Wei-Chun Cheng 1, 2 , Cheng-Lung Hsu 3 , Xiujun Cai 4 , Chawnshang Chang 2, 4, 5 , Wen-Lung Ma 1, 2 1 Graduate Institution of Clinical Medical Science, and Graduate Institution of Cancer Biology, China Medical University, Taichung 40403, Taiwan 2 Sex Hormone Research Center, Organ Transplantation Center, Research Center for Tumor Medical Science, and Department of Gastroenterology, China Medical University/Hospital, Taichung 40403, Taiwan 3 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung University/Memorial Hospital, Taoyuan 333, Taiwan 4 Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China 5 George Whipple Laboratory for Cancer Research, Department of Pathology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14623, USA Correspondence to: Wen-Lung Ma, email: maverick@mail.cmu.edu.tw Chawnshang Chang, email: chang@urmc.rochester.edu Keywords: AR, HCC recurrence, CTC, CD90, anoikis Received: December 15, 2015 Accepted: May 28, 2016 Published: June 20, 2016 ABSTRACT Purpose: Although hepatectomy and liver transplantation surgery for hepatocellular carcinoma (HCC) are effective treatment modalities, the risk of recurrence remains high, particularly in patients with a high number of circulating tumor cells (CTCs) expressing cancer stem/progenitor cell markers. Androgen receptor (AR) signaling has been shown to suppress HCC metastasis in rodent models of HCC. In this study, we investigated whether AR is associated with postoperative HCC recurrence. Experimental Design: CTCs were obtained from patients with HCC who had undergone hepatectomy to investigate whether they are associated with disease outcome. AR knockout was introduced in two mouse models of spontaneous HCC (carcinogen- and hepatitis B virus-related HCC) to delineate the role that AR plays in HCC recurrence. Biological systems analysis was used to investigate the cellular and molecular mechanisms. Results: We found that the expression of AR in CTCs was negatively associated with HCC recurrence/progression after hepatectomy. Our results suggest that AR-mediated suppression of HCC recurrence/progression is governed by a three-pronged mechanism. First, AR suppresses the expression of CD90 in CTCs by upregulating Histone 3H2A. Second, AR suppresses cell migration at the transcriptome level. Third, AR promotes anoikis of CTCs via dysregulation of cytoskeletal adsorption. Conclusions: The results indicate that AR expression may be the gatekeeper of postoperative HCC recurrence. Therefore, targeting AR in presurgical down-staging procedures may serve as a secondary prevention measure against HCC recurrence in the future.