膀胱癌為台灣常見的癌症之一。在烏腳病流行及長期飲用含砷量高的井水的地區，罹患膀胱癌的比例明顯增加。但是引起膀胱癌的致病機轉仍然不清楚。在我們的實驗室，利用微陣列技術分析人類正常膀胱移形上皮細胞株 E6 和外送入帶有H-ras過度表現的細胞株 E6RC，發現在一連串被Ras所活化的基因中有一個基因命名為Lu。Lu為一血型抗原，屬於免疫球蛋白基因家族的一員。利用免疫染色發現，Lu主要分佈在膀胱癌細胞的細胞膜上，且Lu的表現量和腫瘤的分化等級呈正相關。暗示Lu在膀胱癌的發生過程中扮演一個重要的調節角色，但是詳細的機制仍然不清楚。本研究發現到，活化的Ras可以活化Lu 啟動子，進而造成Lu基因的過量表現。此外以一株持續表現Lu基因的老鼠纖維母細胞株NIH-Lu，進一步探討Lu在膀胱癌發生過程中所影響的生物特性及相關的訊息傳遞。我們的結果顯示，Lu過度表現可使細胞轉形。當Lu和它的受體laminin結合後，會活化PI3K/Akt訊息傳遞路徑，對抗MTX所引起的細胞計畫性凋亡(apoptosis)。Lu也會藉由和它的受體作用活化Erk/MAPK 訊息路徑，進而活化下游Rho之活性，但是抑制Rac的活性，而改變細胞骨架，增加stress fiber的形成和細胞黏附的能力。對於Lu基因的研究及了解，可幫助發展新的方法治療Lu基因度表現的膀胱癌細胞。

　　Bladder cancer is one of the most frequently occurred cancers in Southern Taiwan and has a positive correlation with black foot disease and arsenic exposure. However, the underlined mechanism of bladder carcinogenesis remains unknown. Using microarray assay, we identified a Ras oncogene up-regulated membrane protein designated Lutheran, a blood group antigen (Lu), which is a member of the immunoglobulin superfamily. Our preliminary data showed that Lu expression was detected around the membrane of bladder cancer cells and demonstrated a positive correlation of Lu expression with histological grading, suggesting that Lu may play a pivotal role in the tumorigenesis of human bladder. However, the role of Lu in bladder cancer has not been reported. In this study, the relationship between Ras and Lu was confirmed using a Lu promoter driven luciferase reporter system. Furthermore, to reveal Lu-related biological responses in bladder cancer cells, we constructed a plasmid encoding human Lu, designated pcDNA3.1-Lu, and introduced it into NIH3T3 cells to establish a stable cell line, NIH-Lu. We demonstrated that over-expressed Lu induces cell transformation. Additionally, interaction of laminin and Lu suppresses the MTX-induced apoptosis through PI3K/Akt signaling pathway. In this study, we provide the first evidence that interaction of laminin and Lu utilize Erk/MAPK pathway to coordinative regulate Rho and Rac which control cell adhesion and stress fiber formation. This study highlights the potential of Lu as a bio-target for anticancer therapy.

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