腫瘤微環境中由不同的細胞組成，其中腫瘤相關巨噬細胞可以產生各種因子影響微環境並促進腫瘤發展。TGF-β1可由脂肪內的巨噬細胞產生影響癌症進展，包含上皮間質轉化（EMT）、癌症幹細胞性質和抗藥性。CUB domain-containing protein 1（CDCP1）是一種穿膜蛋白。CDCP1在腫瘤細胞中表現較高。 全長CDCP1（flCDCP1）可被切割為切割形式CDCP1（clCDCP1）。近期研究發現，flCDCP1能夠增強TGF-β1調控基因的表達，因為其細胞外CUB結構域可以結合TGF-β1，然後增強TGF-β1誘導的下游信號傳遞。全長CDCP1（flCDCP1）可被切割為切割形式CDCP1（clCDCP1）。最近的研究發現，flCDCP1能夠增強TGF-β1信號傳遞的活性，因為其細胞外CUB結構域可以結合TGF-β1，增強TGF-β1下游訊息傳遞路徑。因此，在本篇研究我們比較高度表達flCDCP1及clCDCP1的尿路上皮癌細胞對腫瘤微環境中TGF-β1下游訊息傳遞路徑的影響。我們檢測PAI-的表現，PAI-1是一種絲氨酸蛋白酶抑制劑，能抑制CDCP1被切割並使flCDCP1表現上調。我們使用球狀形成實驗來檢測flCDCP1和clCDCP1之間的幹細胞特性。此外，我們還進行了藥物敏感性測試，研究flCDCP1在Gemcitabine抗藥性中的作用。結果顯示，高度表現flCDCP1可以促進癌細胞的幹細胞特性及抗藥性。綜上所述，flCDCP1可以與TGF-β1調控路徑互助，促進尿路上皮癌細胞惡化。

The tumor microenvironment consists of various types of cells, including tumor cells, tumor stromal cells, and immune cells. Tumor-associated macrophage (TAM) is one of the important cells that secretes factors to alter the condition and promote tumor progression. a. Transforming growth factor-β1 (TGF-β1), which TAM can produce, plays a significant role in cancer progression, influencing processes such as epithelial–mesenchymal transition (EMT), cancer stemness, and drug resistance. The transmembrane CUB domain-containing protein 1 (CDCP1) is upregulated in multiple solid tumors. Full-length CDCP1 (flCDCP1) can be cleaved into cleavage form CDCP1 (clCDCP1). Recently, CDCP1 was found to enhance TGF-β1 target gene expression, as its extracellular CUB domain can bind to TGF-β1 and then enhance TGF-β1-induced downstream signaling. Therefore, we generate stable cell lines expressing flCDCP1 and clCDCP1 to compare their impacts on the downstream functions of TGF-β1 signaling in the tumor microenvironment (TME). This evaluation involves examining the expression of plasminogen activator inhibitor-1 (PAI-1). PAI-1 is a serine protease inhibitor that can inhibit the cleavage of CDCP1, leading to an increased expression of flCDCP1. The evaluation of stemness properties between flCDCP1 and clCDCP1 is conducted using the sphere formation assay. Moreover, a drug sensitivity assay was conducted to investigate the role of flCDCP1 in gemcitabine resistance. The results show that flCDCP1 promotes cancer stemness and gemcitabine resistance. Hence, we conclude that flCDCP1 cooperates with TGF-β1 signaling to enhance cancer progression in UC cells.

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