臺灣博碩士論文加值系統

尿路上皮癌 (Urothelial carcinoma, UC) 在美國男性癌症中排名第四，其發病率在全球不斷增加。由於尿路上皮癌的高復發率並且會進展到晚期，因此特定生物標誌的發現有利於尿路上皮癌的患者。CUB Domain-containing Protein 1 (CDCP1) 是一種細胞表面跨膜蛋白。越來越多的證據表明CDCP1 在各種人類癌症中過度表達。 CDCP1 可以在細胞表面以全長和/或裂解形式表達。在全長CDCP1的細胞膜外區域有胰蛋白酶和絲氨酸蛋白酶的切割位置。在被絲氨酸蛋白酶切割後，全長CDCP1失去了第一個CUB domain並變成裂解的CDCP1。纖溶酶原激活劑抑制劑 1 (PAI-1) 是一種絲氨酸蛋白酶抑制劑，可被腫瘤細胞分泌到胞外微環境中並在纖溶酶原激活劑系統中扮演重要的角色。 PAI-1 可與尿激酶纖溶酶原激活劑 (uPA) 結合，從而抑制 uPA 的裂解功能。然而，CDCP1 和 PAI-1 之間的交互作用尚不清楚。因此在我們的研究中，我們利用 TGFβ1 刺激尿路上皮癌細胞，發現全長的CDCP1增加，但裂解的CDCP1卻減少。這種現象在其他癌細胞中也觀察得到。此外，我們還發現PAI-1在 TGFβ1 刺激後有上升的現象。而且全長CDCP1過表達的尿路上皮癌細胞具有更高的 PAI-1 和上皮細胞間質轉化 (EMT)標誌物的表達，這些標誌物在 TGFβ1 刺激後會被誘導。另外，全長CDCP1過表達的尿路上皮癌細胞具有更好的轉移和傷口癒合能力。綜合上述結果，我們推測 PAI-1 參與了 TGFβ1 調節 CDCP1的裂解過程，並且在尿路上皮癌細胞中全長CDCP1相較於裂解的CDCP1具有更好的促進細胞移動和上皮細胞間質轉化的能力。
關鍵字：尿路上皮癌

Urothelial carcinoma (UC) ranks fourth in men among all cancers in the United States of America and its incidence increasing worldwide. Due to the high recurrence rate of UC and the progression to the advanced stage, findings of specific biomarkers are benefit to UC patients. CUB Domain-containing Protein 1 (CDCP1) is a cell surface transmembrane protein. Accumulating evidence showed that CDCP1 was overexpressed in various human cancers. CDCP1 can be expressed at the cell surface as a full-length (flCDCP1) and/or a cleaved form (clCDCP1). There are trypsin and serine protease cleavage sites at the extracellular domain of flCDCP1. After cleaving by serine proteases, flCDCP1 loses its domain 1 and leads to the formation of clCDCP1. Plasminogen activator inhibitor 1 (PAI-1) is a serine protease inhibitor which can be secreted into the extracellular microenvironment by tumor cells and plays an important role in plasminogen activator system. PAI-1 can interact with urokinase plasminogen activator (uPA) for inhibiting the proteolytic cleavage function of uPA. However, the crosstalk between CDCP1 and PAI-1 is not well known yet. In our results, we treated UC cells with TGFβ1 and found that flCDCP1 was increased, but the clCDCP1 was decreased. The pattern was also observed in other cancer cells. In addition, we also found that PAI-1 was upregulated after TGFβ1 treatment. Moreover, flCDCP1-overexpressed UC cells showed higher expression of PAI-1 as well as epithelial mesenchymal transition (EMT) markers, which were induced after TGFβ1 treatment. Besides, flCDCP1-overexpressed UC cells had a better ability of migration and wound healing. Taken together, we suggest that PAI-1 is involved in the TGFβ1-regulated CDCP1 cleavage in UC cells and flCDCP1 has a better ability to promote cell motility and EMT than clCDCP1 does.
Keywords：urothelial carcinoma, CDCP1, TGFβ1, PAI-1

Abstract I
摘要 II
致謝 III
Index IV
Contents V
Introduction 1
Hypothesis and Specific Aim 6
Materials and Methods 7
Results 22
Discussion 27
Figures 30
References 47
Appendix 50
List of Figures VI
List of Appendix VII
List of Abbreviations VIII

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