| 摘要: | 卵巢癌(ovarian cancer)經常發生於三種常見的卵巢細胞中，包括上皮細胞、生殖細胞以及基質細胞。其中屬卵巢上皮細胞癌最為惡性，根據組織病理學的分析，卵巢上皮細胞癌可分為四種次類型，包括：漿細胞癌(serous,~75%)、黏液腺癌(mucinous, ~3%)、子宮內膜狀癌(endometrioid, ~10%)以及亮細胞癌(clear cell, ~10%)。癌幹/前驅細胞(cancer stem/progenitor cells)具有無限制自我更新複製以及抵抗藥物的特性，因此它被認為是造成癌症發展的一個複雜因子。男性荷爾蒙受體(androgen receptor)存在於細胞質內，當它與男性荷爾蒙(androgen)結合後，會被活化而進入到細胞核內啟動基因的表現，因此也普遍被認為是轉錄因子。目前研究已知，男性荷爾蒙受體與卵巢癌的發展有關，而且許多男性荷爾蒙受體的拮抗劑已被使用來治療卵巢癌。然而，這些藥物對於卵巢癌患者的治療仍然存在許多爭議。在本研究中，我們探討男性荷爾蒙受體在卵巢癌幹/前驅細胞以及抗藥性中所扮演的角色，進而研究其可能作為卵巢癌合併治療藥物之可行性。第一篇的研究發現，卵巢畸胎瘤(ovarian teratoma)細胞中的男性荷爾蒙受體，不需要透過與荷爾蒙的結合，本身便具有活性來促進畸胎瘤癌幹細胞群的增生以及自我更新能力。為了更進一步的探討男性荷爾蒙受體活性的特異性機制，在第二篇的研究中顯示，一種具有調節基因表現的小分子核糖核酸，mir-21(microRNA-21)間接地影響男性荷爾蒙受體的表現。此外，本篇研究中，透過細胞轉染改變卵巢畸胎瘤細胞內mir-21的表現，發現mir-21本身會影響畸胎瘤癌幹細胞的自我增生能力，進而促進細胞生長。根據在卵巢癌畸胎瘤所獲得的研究成果，第三篇於卵巢上皮細胞次類型漿細胞癌的研究中，發現了男性荷爾蒙受體調控轉錄的新機制。研究顯示，用於治療卵巢癌患者的第一線用藥，紫杉醇(paclitaxel)會促進男性荷爾蒙受體的活化，並且與芳香?受體(aryl-hydrocarbon receptor, AhR)結合，進入到細胞核內調控ABCG2的表現，同時也促進了癌細胞對藥物的抗藥性。在進一步的細胞與動物實驗中顯示，唯有使用藥物迫使癌細胞內的男性荷爾蒙受體降解，同時與紫杉醇化療藥物進行合併治療，才能更有效的抑制卵巢上皮細胞次類型漿細胞癌細胞的生長。綜上所述，我們的研究成果提供了一個新的概念作為卵巢癌治療策略之發展。
Ovarian cancer (OVCA) arise from three cellular origin, including surface epithelial cells, germ cells, and stromal cells. The most lethal OVCA is epithelial onarian cancer (EOC) which can be divided into four histological subtypes, including serous carcinoma (SC, ~75%), mucinous carcinoma (MC, ~3%), endometrioid carcinoma (EC, ~10%) and clear cell carcinoma (CCC, ~10%). Cancer stem/progenitor cells (CSPCs) are considered cancer promoter for their capacity of unlimited self-renewal and drug resistance. Androgen receptor (AR) belongs to nuclear receptor superfamily, which activation through biunding with androgens. AR has been suggested to play role in OVCA development. In the thesis, an ligand-independent AR function to enriches CSPCs (e.g., CD133+) via facilitated self-renewal in ovarian teratocarcinoma cells (OVTC, germ cell tumors) was demonstrated. Moreover, an OVTC promoter roles of onco-miR (miR-21) had been associated with AR expression. The miR-21 itself is essential for promoting cell growth through sustaining CSPCs. On the other hand, the pathological roles of AR in SC-EOC was characterized. The AR and ABCG2 were colaterally expressed in SC-EOC lesions. The AR expression is linked to SC-EOC of taxel treatment modality to poor prognosis. Palitaxel treatment could turn on AR tranactivation function in vitro, of which explained the paclitaxol resistence in molecular aspect. The mechanistic dissection has delineated a paclitaxol-AR/AhR (aryl-hydrocarbon receptor)-ABCG2 regulatory axis in SC-EOC cells. For the translational approach, the ASC-J9 (AR degradation enhancer) treatment could resensitize paclitaxel-resistance SC-EOC in vitro and in vivo. Therefore, the utilization of ASC-J9 for OVCA therapy is vivid in the future. In conclusion, this thesis summarized the roles of AR play in OVCA disease development in cellular and molecular levels. This thesis illustrated the mode-of-action for ASC-J9 pharmaceutical development. |
