2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657063摘要：我們已發表一人類卵巢類子宮內膜上皮細胞癌（OEC）細胞株侵襲模式，並經由此類模式得知IGFBP-3 為抑制侵襲基因，且IGFBP-3 為OEC 病人預後重要因素。進一步的，我們以微陣列分析，發現IGFBP-3 上升伴隨TSP-1 的表現，TSP-1 為一抑制血管新生蛋白。首先我們建立一可經由藥物引發IGFBP-3 的OEC 細胞株，經由人類臍帶細胞及雞胚胎血管形成實驗發現，IGFBP-3 的確也扮演抑制血管新生的角色。我們推測，IGFBP-3 透過調控TSP-1 而達到抑制血管新生。另外，經由裸鼠轉殖實驗發現，IGFBP-3 表現時，腫瘤呈現「休眠」狀態。但在經過數日，腫瘤經由某些未知機制而克服血管抑制之狀態，再度形成血管，腫瘤恢復成長，即所謂的angiogenic switch。在本計畫，我們將研究IGFBP-3 和TSP-1 之間的關係，從而得知兩者如何協調達成抑制血管新生的目的。另外，我們也研究IGFBP-3 調控TSP-1 的機制，區分是直接或間接由其他轉錄因子來調控TSP-1 promoter。有趣的是，我們由之前NSC 研究計畫發現在OEC 的病理形態中IGFBP-3 和PTEN 之間的關係非常密切，以siRNA 抑制PTEN 後，可經由VEGF 的調控而造成大量血管新生。已知TSP-1 為抑制血管新生重要蛋白，而VEGF 為促進血管新生最重要的蛋白，兩者互相拮抗而達成腫瘤血管新生狀況。因此，我們由OEC裸鼠腫瘤PTEN 調控VEGF 改變血管新生的結果推測，表現IGFBP-3 之腫瘤出現angiogenic switch 的機制與PTEN 和VEGF 有關，並經由此機制達到腫瘤侵襲及轉移。在本計畫我們將進一步尋找參與angiogenic switch 的蛋白，並探討其機制及臨床上的重要性，我們最終目的在尋找抗血管新生機制在卵巢癌治療上的應用。<br> Abstract: We have established an ovarian endometrioid carcinoma (OEC) invasion cell line modeland have identified IGFBP-3 as an invasion suppressor gene in OEC. In clinical OEC cases,IGFBP-3 is a key factor correlated to patient outcome. By microarray analysis, we furthernoticed that IGFBP-3 expression is strongly correlated with expression of TSP-1, anangiogenesis inhibitor. In our preliminary study, we have established an inducible IGFBP-3cell line and performed angiogenesis studies, including HUVE and CAM assays.We foundIGFBP-3 function as an angiogenesis inhibitor, probably through TSP-1 regulation. Byheterotransplantation study, we observed that tumor with IGFBP-3 expression showed a stateof tumor dormancy. However, the xenograft tumor somehow managed to escape from theinhibition of angiogenesis through an angiogenic switch, whose mechanism is still unclear. Inthis proposal, we plan to study the coordinate regulation of IGFBP-3 with TSP-1 onangiogenesis inhibition.We will also analysis the mechanism of IGFBP-3 regulation onTSP-1 promoter, either directly or indirectly through other transcription factors. In ourprevious NSC study, we found IGFBP-3 expression closely associated with PTEN expressionin the pathogenesis of OEC. Suppressing PTEN using siRNA is associated with profoundtumor vascular formation, through VEGF regulation. Since TSP-1 acts against VEGF onangiogenesis regulation, our data suggests that PTEN and VEGF may play some role in theangiogenic switch in OEC, and furthermore, to tumor invasion and metastasis. In this study,we plan to identify proteins involved in the angiogenic switch and the mechanism of howtumor accompanied this angiogenic switch.We will also study the expression of theseangiogenesis associated proteins in OEC cases.We aim to search the therapeutic role ofanti-angiogenesis in the treatment of ovarian cancer.子宮內膜上皮細胞癌侵襲基因血管新生蛋白質組學分析ovarian endometrioid carcinomaIGFBP-3. TSP-1Calreticulinangiogenesisinvasion