尿路上皮癌 (urothelial carcinoma, UC) 是指在泌尿系統中所發生的癌症，其發生位置可能是腎盂、輸尿管、膀胱等尿路途徑，其中又以膀胱癌最為常見。根據美國統計男性最常見的癌症中，尿路上皮癌位居第四名。尿路上皮癌後期或是罹患轉移性尿路上皮癌的患者常常使用複合藥物進行化療，其中，gemcitabine因為毒性較低而被作為一線藥物使用，然而有越來越多的患者表現出對gemcitabine的抗藥性，這使得尿路上皮癌在治療上愈發困難，復發率也逐年攀升，至今已有高達70%的復發率，因此，了解gemcitabine抗藥性的機制將有助於發展有效的尿路上皮癌治療策略。CUB Domain-containing Protein 1 (CDCP1) 為一個表現於細胞膜的跨膜醣蛋白，我們將尿路上皮癌細胞株T24與其抗藥性細胞株T24-GR進行比較，發現抗藥性細胞株中有較高的CDCP1蛋白表現量，因此在本篇研究的實驗中，我們將探討CDCP1與gemcitabine抗藥性的關聯性。我們利用轉染技術在細胞中過度表現CDCP1，同時也使用CRISPR/Cas9的技術將細胞中的CDCP1剔除，我們發現過度表現CDCP1的細胞株具有較高的gemcitabine抗藥性，此外，CDCP1過度表現的細胞表現出更高的腫瘤成球能力、轉移能力和失巢凋亡抗性，而這些功能性檢測能力在CDCP1剔除的細胞則有較低的表現。另外， TGFβ1可能阻斷尿路上皮癌細胞中CDCP1的裂解，此機制有待進一步闡明。綜上所述，我們推測CDCP1會參與調控尿路上皮癌細胞的抗藥性，並且會促進細胞產生較高的幹細胞特性、細胞轉移能力以及對失巢凋亡的抗性。

Urothelial carcinoma (UC) is the fourth common cancer in men in the United States of America. Patients with advanced or metastatic UC are usually treated with systemic chemotherapy using multidrug regimens. Gemcitabine has been proven as a first-line drug in UC because of its low toxicity profile. However, more and more UC patients express no response to gemcitabine in the therapies. This reveals the needs for the understanding of the mechanisms of gemcitabine resistance, which might develop a novel strategy for effective treatment. CUB Domain-Containing Protein 1 (CDCP1) is a transmembrane cell surface glycoprotein and overexpresses in some cancers. In our results, we overexpressed and silenced CDCP1 in UC cells by using CRISPR/cas9, respectively. CDCP1-overexpressed UC cells exhibited resistance to gemcitabine while CDCP1-silenced UC cells had lower resistance to gemcitabine. Moreover, CDCP1-overexpressed UC cells showed higher ability of tumor sphere formation, migration and anoikis resistance, and CDCP1-silenced UC cells showed lower ability of these functional assays. Furthermore, TGFβ1 might prevent the cleavage of CDCP1 in T24 cells. The mechanism needs to be further elucidated. Taken together, we suggest that CDCP1 might play a role in the gemcitabine-resistant UC cells. In addition, CDCP1 might also participate in the progression of UC, such as increasing migration ability, anoikis resistance and formatting tumor spheroids.

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