2013-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643513摘要：LEF1 是 β-catenin 的結合伙伴，用以將 Wnt 訊息傳遞到細胞核，以啟動下游基因的轉錄。已有許多論文研究 β-catenin 的磷酸化，降解，和核轉位。但 LEF1 的功能 和其調節機制很少被人研究，在本計劃中，我們發現：(1). LEF1 在多種上皮癌過度表現，特別是雌性素受器陽性的癌症。(2). LEF1 會被肝細胞生長因子(HGF)誘導產生。我們將以各種訊息傳導途徑的抑制 物找出其詳細途徑，再以染色質免疫沉澱證明此途徑是直接作用在 LEF1 的驅 動子。並以 Boyden 室侵犯試驗證明 LEF1 是 HGF 誘導腫瘤侵犯所必須的。(3) LEF1 會被雌性素誘導產生。此外，LEF1 可能和雌性素受器結合。此結合會影 響雌性素受器的穩定性，並且可能會影導雌性素受器對下游基因的調控。我們 也將以各種體內和體外的生長試驗證明 LEF1 會影響雌性素受器陽性乳癌的生 長。<br> Abstract: LEF1 is a binding partner of β-catenin. Its role is to transduce Wnt signal to nuclei to turn on the transcription of downstream target genes. Numerous researches have focused on the study of phosphorylation, degradation, and nuclear translocation of β-catenin. However, the function of LEF1 and the mechanism for regulation of its expression haven’t been extensively studied. In this proposal, we will find:(1) LEF1 is overexpressed in multiple types of epithelial cancers, especially estrogen receptor-positive cancers.(2) LEF1 can be induced by hepatocyte growth factor (HGF). We will use various inhibitors of signal transduction pathways to identify the detailed mechanism. Besides, we will use chromatin immunoprecipitation to prove direct regulation of LEF1 promoter by these pathways. Boyden chamber invasion assay will be used to prove that induction of LEF1 expression is essential for HGF-induced tumor invasion.(3) LEF1 can be induced by estrogen. Besides, LEF1 probably binds to estrogen receptor. The binding will affect the stability of estrogen receptor and the regulation of the expression of downstream targets of estrogen receptor. We will use various in vitro and in vivo growth assays to prove the role of LEF1 on the growth of estrogen receptor-positive tumors.