研究背景及目的：
雖然肝切除和肝移植手術是有效的治療肝細胞癌（HCC）方法，但復發的風險仍然很高，特別是在患者有較高的循環腫瘤細胞（CTC），且呈現出腫瘤幹細胞或原始細胞標記的患者。已知雄激素受體（AR）信息已被證實在老鼠肝癌模型可以減少肝癌細胞的轉移；我們研究的主要目的，雄激素受體是否與肝癌手術後的復發有關係因為這個關係還未被證實。
實驗設計：
從施行切肝手術肝癌患者的血液中去測量循環腫瘤細胞，以證實循環腫瘤細胞與疾病進展的相關性。在動物的模型方面，則使用兩種雄性受體剔除(AR knockout)的自發性肝癌老鼠，其中包含致癌物與B型肝炎基因轉殖老鼠模型(carcinogen-and hepatitis B virus-related HCC)去分析雄性激素受體在肝癌患者復發扮演的角色；並使用系統生物學研究與分析方法，去探討雄激素受體在細胞與分子層面的相關機轉。
研究結果：
我們發現在循環腫瘤細胞中雄激素受體與接受肝癌切肝患者術後的復發及肝癌疾病的進展是負相關。我們的結果顯示雄激素受體支配下的肝癌復發與進展，主要通過以下三管齊下的調控機制。第一，雄激素受體通過上調組蛋白3H2A而去抑制循環腫瘤細胞CD90的表現，第二，雄激素受體在轉錄體的層級去抑制細胞遷移，第三，雄激素受體經由細胞骨架吸收的失調而促進循環腫瘤細胞漂亡。
結論：
這些結果顯示，雄激素受體的表現可能是肝癌手術後復發的守門者。因此，未來在手術前降階的處理上，可以標靶雄激素受體以作為減少肝癌復發的二級防護措施。
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.
