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

Abstract

PurposeAlthough 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 DesignCTCs 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.ResultsWe 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.ConclusionsThe 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.

Sex Hormone-Dependent Physiology and Diseases of Liver

“…In this area, the results of a study performed on two AR knockout mouse models with spontaneous HCC, which showed a negative relation between HCC recurrence/progression after hepatectomy expression of AR in CTCs, are very interesting and promising. AR-regulated suppression of HCC is a solid sign that this receptor could act as a gatekeeper of HCC recrudescence after surgery [144].…”

Metronomic Celecoxib Therapy in Clinically Available Dosage Ablates Hepatocellular Carcinoma via Suppressing Cell Invasion, Growth, and Stemness in Pre-Clinical Models

“…CSPCs have extensive self-renewal ability, tumorigenesis, and differentiation potential; consequently, they give rise to new anaplastic tumor cells that exhibit resistance to cytotoxic chemotherapy and ionizing radiation (32,33). This resistance may be attributed to their presumably slow cell cycle and overexpression of efflux pumps (34), which gives rise to CSPC subpopulations within each tumor (19,32,33,35). Given the essential role of CSPC in metastasis, recurrence, and therapeutic resistance, it becomes imperative to identify novel therapies, specifically targeting CSPCs, which can potentially eradicate the renewal capacity of the tumor (36).…”

“…The HBVtg-HCC mouse model was established and characterized as described earlier. (18)(19)(20) In brief, the HBVtg mice were intra-peritoneally (i.p.) injected with a carcinogen (diethylnitroasamine; DEN; 20 mg/kg) on the 14 th days of pup mice.…”

Low-Density Lipoprotein Receptor-Mediated Lipidome-Transcriptome Reprogramming Impulses to Cisplatin Insensitivity

“…For general histologic inspection, we treated the tissue sections (2 μM) with hematoxylin and eosin or stained the sections with antibodies specific for LDLR and LPL with an ABC kit (Vector Laboratories) to enhance the staining signals. Staining intensity was scored according to the Allred scoring system (Hammond, Hayes et al, 2010, Nose, Sugio et al, 2009 and our previous work (Lai, Yeh et al, 2016). The proportion of cells that stained positive for LDLR and LPL was graded using a five-point scale according to the proportion of positive cancer cells (1: < 1/100; 2: 1/100 to 1/10; 3: 1/10 to 1/3; 4: 1/3 to 2/3; and 5: > 2/3).…”

“…With regard to the web-based KMplotter platform used for the evaluation of the hazard ratio (HR) scores of the pathways (cluster of genes) with respect to patient survival, the following previously established formula was used (Chang et al, 2017, Chang, Huang et al, 2016:…”