| 摘要: | 雄激素受體（AR）是一種轉錄子，在與荷爾蒙相關之癌症，例如攝護腺癌是扮演著重要的角色。雄激素受體在攝護腺的表皮細胞可作為一種抗細胞淍亡的存活因子，而且在雄激素受體受到活化時，更可能使攝護腺開始癌化。目前針對轉移性攝護腺癌，雄激素剝奪之荷爾蒙療法（Androgen deprivation therapy）被視為重要的治療方法，但往往在經過治療的兩，三年後即產生閹割抗性攝護腺癌（castration resistance prostate cancer）。雄激素受體除了被認為是一種致癌基因外，現在己有很多的證據指出在攝護腺癌之演變過程中，同時有扮演抑癌基因的功能，但確實的分子機轉尚未清楚。在本實驗中，發現活化的雄激素受體可以誘導miR-203或miR-1，從而使SRC或TCF7受到抑制，造成攝護腺癌細胞的增生與活動力下降。實驗發現雄激素受體被活化後，能與miR-203或miR-1促進子上的雄激素受體反應序列結合以促進該微小核醣核酸之轉錄作用。之後，亦發現miR-203或miR-1可以與SRC 或 TCF7 的信息核醣核酸上3’UTR序列結合以抑制SRC & TCF7的轉錄作用和減少該兩種基因產生的蛋白質。透過人體資料庫數據與病人檢體的分析，可發現雄激素受體、miR-203、miR-1與SRC或TCF7有負相關之關係。當攝護癌細胞被活化miR-203或miR-1以導致SRC或TCF7表現下降時，細胞的惡性表現也同時減緩。基於我們的實驗結果，發現了一個新的分子路徑機轉，雄激素受體能誘導miR-203或miR-1表現並抑制SRC或TCF7表現，此機轉能說明雄激素受體具備抑癌基因的能力，並能嘗試部份解釋荷爾蒙療法失敗的原因。
Androgen receptor (AR), a transcription factor, is a critical factor in hormone-related cancers such as prostate cancer (PCa). AR is an anti-apoptosis survival factor for prostate epithelial cells and increasing AR activity is considered as a stimulator for PCa initiation. Androgen deprivation therapy (ADT) is the only strategy for metastatic PCa treatment but most metastatic PCa will recur and resist to ADT within 2 to 3 years . Besides as an oncogene related to PCa, accumulating evidences are shown that activated AR also acts as a tumor suppressor during PCa progression but molecular mechanisms is still to be determined. In our studies, we demonstrated that activated AR inhibited PCa proliferation and motility via tumor suppressor microRNA (miR) mediating SRC and TCF7 down-regulation. Activated AR under dihydrotestosterone (DHT) treatment enhanced AR binding to androgen receptor response elements (AREs) in stem loop promoter region of miR-203 and miR-1 which promoted their transcription. miR-203 and miR-1 can directly bind to 3’UTR of SRC and TCF7 mRNA to repress translation and reduced their mRNA and protein level respectively. Using clinical datasets and specimens analysis, we found positive correlation among AR, miR-203, and miR-1 and negatively correlation between miR-203 and SRC, and miR-1 and TCF7. Loss of malignant phenotype of PCa was shown if miR-203 or miR-1 overexpressed to downregulate SRC and TCF7. Herein, we depicted a novel mechanism that AR played a tumor suppressor role by upreguating miR-203 and miR-1 to suppress SRC and TCF7 expression and provided a possible mechanism to explain how PCa relapse after ADT. |
