2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648766摘要：MicroRNA (miRNA)為近年來發現的調控分子，大小約22nt, 與targetmRNA 上的互補序列進行結合後，進一布調控基因表現。至今約有400 個以上的miRNA 陸續被發現。miRNA 在發育、分化、病毒感染、免疫反應，以及癌化等各種生物過程中皆扮演重要角色。血管新生為腫瘤生長、轉移過程中的重要步驟，在癌症進程中相當關鍵，並且受到各種調控，如缺氧以及生長因子。雖然近年來有許多研究關於miRNA 在腫瘤上扮演的角色，但其中仍缺乏與miRNA 調控腫瘤血管新生相關之研究。HIF-1α 為血管新生過程中重要之轉錄因子，其傳統之分子調控機制也已知之甚詳。在缺氧狀態下(oxygen-dependent)，HIF-1α 會增加其穩定性並轉移至細胞核內，進而活化下游基因如VEGF, IL-8, bFGF；另外，HIF-1α 蛋白之生合成同時也受到生長因子的刺激(oxygen-independent)。然而，目前仍相當缺乏對於miRNA 調控HIF-1　以及腫瘤血管新生之相關研究。有鑑於此，本計畫目標為建立嶄新之分析篩選平台，全面性地探討miRNA 調控HIF-1α 之詳細機制，及其參與腫瘤血管新生過程之功能性角色。<br> Abstract: MicroRNA (miRNA), small noncoding RNAs of ~22 nucleotides, belong to anovel class of gene regulatory molecules that negatively control gene expression bybinding to complementary sequences on target messenger RNAs (mRNAs)1. Until now,~400 of miRNAs have been found in metazoan and some of them have been functionallyvalidated. All these evidences indicate that miRNA is the critical regulator for geneexpression and biological functions such as development, differentiation, carcinogenesis,virus infection, and immune response2-4. Angiogenesis is a fundamental process duringtumor growth and metastasis5. The activation of angiogenesis is a critical step in cancerdevelopment , involving several kinds of stimulation such as hypoxia and growthfactors5-6. Although miRNAs play important roles in cancer development, only few ofthem have been identified as an angiogenesis regulator. The gatekeeper of tumorangiogenesis, hypoxia-inducible factor (HIF)-1α, is a pivotal transcription factor whichregulates angiogenesis by inducing growth factors such as VEGF, IL-8, and bFGF7. Underhypoxic conditions, stabilized HIF-1α is translocated into the nucleus and activatesdownstream genes. Several studies have demonstrated that de novo synthesis of HIF-1α isregulated via oxygen-independent mechanisms such as growth factors (e.g., HGF, EGF,and Cyr61) 8-11. However, it is still unclear how many miRNAs could regulate HIF-1α andtheir functions in tumor angiogenesis. In the three-year project, we would like to explorethe possible miRNAs that regulate the angiogenic activity of cancer cells and themechanisms underlying miRNA-targeted regulation of angiogenesis-related genes. Toaddress the above issues, we firstly will identify which miRNAs can specifically regulatethe expression of HIF-1α, because the importance of both genes in tumor angiogenesishas already been proven. In addition, we also establish in vitro and in vivo model tocharacterize function of HIF-1α binding miRNAs and their regulation bymicroenviromental factors (as described in specific aim 2). We believe that the three-yearproject would provide significant results in understanding the roles of miRNAs in tumorangiogenesis and be benefit for the development of effective anti-cancer angiogenesistreatment.腫瘤血管新生微核醣核酸HIF-1αmiR519c