卵巢癌是一種預後不良以及有很高致死率的婦科惡性腫瘤，其中卵巢上皮細胞癌 (epithelial ovarian cancer) 佔了90％。卵巢上皮細胞癌普遍被認為起源於覆蓋在卵巢表面的表皮層。卵巢上皮細胞癌主要包含有：漿液性卵巢癌 (serous carcinoma)、子宮內膜樣卵巢癌 (endometrioid carcinoma)、黏液性卵巢癌 (mucinous carcinoma) 及亮細胞卵巢癌 (clear cell carcinoma)。

DLK-1是一種屬於類上皮生長因子家族的穿膜蛋白，會在胚胎發育時期大量表現，但仍存在於少數成人的不同種類組織上。DLK-1參與調節脂肪及骨細胞分化，在發育過程扮演重要角色。先前的研究發現，DLK-1在一些不同類型的腫瘤中，有異常的表現量，包括神經母細胞瘤、肝細胞癌、神經膠質瘤及前列腺癌，但在卵巢癌中的表現仍未被深入探討。CD44廣為人知是幹細胞標記，先前有研究指出，CD44在卵巢癌組織的表現量會大幅增加，因此被認為是卵巢癌的生物指標。Vimentin是第三型中間絲蛋白，大量表現於間質組織，並被認為是上皮-間質轉換(epithelial-mesenchymal transition,EMT) 的重要標記。E-cadherin普遍存在於上皮細胞，在腫瘤抑制上有著舉足輕重的角色。E-cadherin的表現量減少，亦涉及於EMT中。

本研究主要在探討DLK-1在不同種類卵巢上皮細胞癌中的表現量以及與腫瘤幹細胞及EMT的相關性。共收集了283個卵巢癌患者的蠟塊，將其製成組織微陣列，並分析其免疫組織化學染色結果。研究結果顯示DLK-1、CD44和Vimentin的表現量，在卵巢癌組織呈正相關 (P ＜ 0.01)；而DLK-1的表現量則與E-cadherin呈負相關，但未達統計意義 (P ＝ 0.237)。研究結果發現，DLK-1在部分卵巢上皮細胞癌也有過度表現，尤其是子宮內膜樣卵巢癌 (Endometrioid carcinoma)。
總括來說，DLK-1可能與EMT及卵巢癌腫瘤幹細胞有關連，DLK-1或可作為卵巢癌預後評估及決定臨床治療方針之生物標記，但仍有待更進一步研究加以證實。

Ovarian carcinoma has poor prognosis with a high mortality rate in gynecologic malignancy. The epithelial ovarian cancers account for 90% of ovarian malignancy. They have been considered arising from the surface epithelium covering the ovary. The major types of epithelial ovarian cancers include serous, endometrioid, mucinous and clear cell carcinomas.

DLK-1(Delta-Like 1 Homolog) is a transmembranous and secreted protein belonging to the epidermal growth factor-like homeotic family. Although expressed widely during embryonic development, only few types of tissue retain DLK-1 expression in adults. DLK-1 plays important roles in regulating cell differentiation, such as adipogenesis and osteogenesis. Aberrant expression of DLK1 has been found in various types of human cancers, including neuroblastoma, hepatocellular carcinoma, glioma and prostate cancer, but its expression in ovarian cancer has not yet been studied.CD44 is known as a stem cell marker. Previous studies showed that CD44 expressed higher level in ovarian cancer tissues and has been identified as a biomarker of ovarian carcinoma. Vimentin is a type III intermediate filament protein that is widely expressed in mesenchymal tissue, and is considered an important marker for epithelial-mesenchymal transition (EMT). E-cadherin is widely expressed in epithelial cells and acts as a pivotal tumor suppressor. Loss of E-cadherin expression has been known to be involved in epithelial-mesenchymal transition.

This study was aimed to discover the significance of DLK-1 expression and its correlation with tumor stemness and EMT in various types of epithelial ovarian cancer. The expression of DLK-1, CD44, vimentin and E-cadherin were analyzed in 283 ovarian carcinomas by immunohistochemistry on tissue microarray. The result showed positive correlation among DLK-1, CD44 and Vimentin expressions (P ＜ 0.01). Although there was no statistical significance (P ＝ 0.237), a reversed correlation was noted between the expressions of DLK-1 and E-cadherin in ovarian carcinomas. Our study revealed that DLK-1 is overexpressed in epithelial ovarian cancers, especially in endometrioid carcinoma.

In summary, DLK-1 may correlate with EMT and tumor stemness of ovarian carcinoma. Further study is needed to assess the potential use of DLK-1 for therapeutic strategy and prognosis evaluation.

論文審定書...........................................................i
摘要................................................................ii
Abstract............................................................iv
第一章 背景介紹......................................................1
1.1 卵巢癌的病因.....................................................1
1.2 卵巢癌的種類.....................................................1
1.3卵巢癌的分期 (FIGO分期系統及TNM) ................................2
1.4 卵巢癌的診斷.....................................................2
1.5 卵巢癌的治療.....................................................3
1.6 DLK-1............................................................4
1.7 CD44.............................................................4
1.8 Vimentin.........................................................5
1.9 E-cadherin.......................................................5
1.10上皮-間質轉換 (epithelial-mesenchymal transition,EMT)............5
1.11 實驗目的........................................................5
第二章 材料與方法....................................................7
2.1 檢體來源.........................................................7
2.2 選取樣本.........................................................7
2.3 組織微陣列 (Tissue microarray)...................................7
2.4免疫組織化學染色 (immunohistochemistry)...........................7
2.5 顯微鏡觀察.......................................................8
2.6 SPSS (Statistical Product and Service Solutions).................8
第三章 結果.........................................................10
第四章 討論.........................................................13
第五章 結論.........................................................16
參考文獻............................................................34
附錄................................................................40

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