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    Title: 雄性激素受體在子宮內膜癌病理生理之探討
    The Pathophysiology Roles of Androgen Receptor in Endometrial Cancer
    Authors: 陳璐敏;Lu-Min Chen
    Contributors: 臨床醫學研究所博士班
    Keywords: 子宮內膜癌;雄激素受體;子宮內膜癌幹細胞;子宮內膜癌細胞抗藥性;芳香烴受體;AR;AR-Q polymorphism;AhR;Endometrial cancer;CD133
    Date: 2018-07-30
    Issue Date: 2018-12-25 10:37:49 (UTC+8)
    Publisher: 中國醫藥大學
    Abstract: 研究背景及目的：
    子宮內膜癌是一種與性荷爾蒙相關的婦女惡性腫瘤。過去的文獻中曾經探討男性激素與男性激素受體可能與子宮內膜癌的惡性發展有關．此外，針對子宮內膜癌細胞對於化療藥物的抗藥性研究中，目前已知可能與一群少量存在於癌細胞內的癌幹細胞有關．我們發現男性激素受體促進癌幹細胞生長，並且與癌藥物抗藥性相關。其中，男性激素受體其基因上含有一個CAG重複片段，此重複片段的長短對於子宮內膜癌細胞的惡性程度，扮演相當重要的腳色。因此，本研究更進一步探討，透過男性激素受體的CAG重複片段與芳香烴受體的交互作用，促進與CD133相關的子宮內膜癌幹細胞生長，進而影響子宮內膜癌細胞的癌症藥物抗藥性。

    實驗設計：
    為了探討男性激素受體與子宮內膜癌幹細胞的癌症藥物Cisplatin (常用子宮內膜癌抗癌藥物)的抗藥性有關連，本實驗使用子宮內膜癌細胞株(Ishikawa cells)來進行探討。首先，我們利用質體轉染的方式，將帶有不同CAG重複長度片段的男性激素受體過度表現於子宮內膜癌細胞株中，同時利用基因啟動子冷光分析實驗，分析CAG重複長度片段的男性激素受體與芳香烴受體之間的交互作用關係。此外，我們也收集了2003年到2006年間，曾經在本院(中國醫藥大學附設醫院)診斷為子宮內膜癌患者的檢體，並分析其男性激素受體的CAG重複片段以及芳香烴受體在患者檢體中的表現，而相關的結果將同時與體外細胞實驗進行比對以及分析。
    研究結果：
    透過體外細胞實驗，我們發現男性激素受體的表現會促進子宮內膜癌細胞株的癌幹細胞族群的數量、癌細胞轉移以及上皮間質轉化。此外，也降低對於癌症藥物Cisplatin的抗藥性的敏感度。我們還發現在患者檢體的分析顯示，男性激素受體 CAG 長度越短，病人預後越差，癌死亡率越高，同時男性激素受體的CAG重複片段表現越短，其細胞內的芳香烴受體表現量反而越高。而體外細胞實驗也證實，在有芳香烴受體配體的存在下，男性激素受體 CAG 長度越短，對於男性激素受體的基因表現越好，同時也會和芳香烴受體產生交互作用，進而調控芳香烴受體基因的表現。

    結論：
    這些結果顯示，男性激素/男激素受體的訊號傳遞，不但會促進子宮內膜癌幹細胞的數量，同時也透過此類癌幹細胞，增加了子宮內膜癌細胞對於抗癌藥物的抗藥性。此外，本研究也指出較短的男性激素受體 CAG 長度，將透過與芳香烴受體產生交互作用，使的子宮內膜癌患者有較差的預後。
    Purpose: Endometrial cancer is sex steroid hormones-related female malignancy. Androgen and androgen receptor (AR) signals have been implicated in endometrial cancer progression. Cancer stem/progenitor cells (CSPC) are suspected linking to chemoresistance in endometrial cancer patients. The AR poly-glutamine polymorphism (AR-Q) was reported to play role in endometrial cancer development. In this study we investigate AR is associated with chemoresistance in endometrial cancer patient via increase CD133 and AR-Q associated with endometrial cancer patients prognosis by interplay with aryl hydrocarbon receptor (AhR)
    Experimental Design: To investigate the AR role in endometrial cancer cell stemness which is related to cisplatin resistance. Ishikawa endometrial cancer cells (high CD133+ expressing cells) were introduced in this study, transfected AR cDNA in the Ishikawa endometrial cancer cells. For AR-Q study, Specimens analyzed were obtained from patients diagnosed with endometrial cancer from 2003 to 2006 at the China Medical University (Taichung, Taiwan), analyzing patient AR-Q polymorphism and AhR expressions. In vitro study, activity of androgen-response element (ARE) and dioxin-responsive element (DRE) with AR-Qs length (Q13 > Q25 > Q35) was compared.
    Results: We found AR expression increased na??ve endometrial cancer side/population (S/P), CSPC population, cell migration, and epithelial- mesenchymal transition (EMT). Meanwhile, it decreased cisplatin cytotoxic effect on endometrial cells. We also found overall survival benefit is ascending with AR-Q lengths (5-year OS of 61.3% in Q length < 20 and 88% in Q length > 23). AhR is higher expressed in short AR-Q tumor compared to that in long AR-Q patient. In vitro study found ARE activity descends with AR-Qs length (Q13 > Q25 > Q35), while BaP suppresses ARE activities in endometrial cancer cells. Furthermore, AR-Q13 (but not AR-Q25, or -35) enhances BaP-induced DRE activity.
    Conclusions: The results indicate that androgen/AR signal could promote endometrial cancer basal CSPC levels. While cancer cells upfront cisplatin treatments, AR might further enhance cells resistance to therapy via increasing CSPC. Also we show that shorter AR-Q has poorer endometrial cancer prognosis. This phenomenon is reversely correlated to AhR expression.
    Appears in Collections:[Graduate Institute of Clinical Medical Science] Theses & dissertations

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