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標題: | HGF藉由活化LEF1轉錄而活化Wnt路徑以促進腫瘤侵襲 HGF activates Wnt pathway by transcriptional activation of LEF1 to facilitate tumor invasion |
作者: | Fang-I Huang 黃芳儀 |
指導教授: | 鄭永銘(Yung-Ming Jeng) |
關鍵字: | 肝細胞生長因子, HGF,Wnt,LEF1, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 肝細胞生長因子(Hepatocyte growth factor, HGF)與其接受體c-Met在癌症的生長與遷移扮演重要的角色。HGF由纖維組織母細胞(fibroblast)分泌,是一個癌症生長與發育的重要中間因子。然而,這其中的機轉尚未清楚。Wnt/β-catenin/Tcf/LEF1 是一條經常在癌細胞中被活化的路徑。利用β-catenin相關路徑的報導基因表現分析,我們發現在肝癌細胞株,肝細胞生長因子會活化β-catenin的路徑。利用微陣列基因表現分析,我們發現LEF1mRNA的表現量被肝細胞生長因子增加了。給予MDA-MB-231細胞株Wortmannin 會抑制HGF誘導的LEF1表現,這代表HGF 誘導LEF1是藉由PI3K/Akt的路徑。我們也給予MDA-MB-231細胞株BAY11-7082及SN50二種專一抑制NF-κB 的抑制劑,也發現可以減少HGF誘導的LEF1表現。利用shRNA敲毀LEF1,會抑制HGF造成的腫瘤侵襲。根據組織免疫染色,我們發現LEF1在各種不同的癌症表現。我們研究顯示,藉由LEF1的轉譯調控,HGF/Met與Wnt/β-catenin/Tcf/Lef之間的訊息傳遞是HGF誘導侵襲的必要條件。 Hepatocyte growth factor (HGF) and its receptor c-Met play important roles in cancer growth and metastasis. HGF is an important fibroblast-secreted protein which is a mediator of cancer development and progression. However, the mechanism is still poorly characterized. Wnt/β-catenin/Tcf/LEF1 pathway is frequently activated in cancers. Using the reporter of β-catenin pathway, we found HGF activates β-catenin pathway in liver cancer cell line HepG2. Using microarray analysis, we found LEF1 expression is enhanced by HGF. Treatment of the MDA-MB-231 cells with wortmannin suppressed the induction of LEF1, indicating that the effect was mediated by signaling through phosphatidylinositol-3-kinase (PI3K)/Akt pathway. We also treated MDA-MB-231 cells with BAY11-7082 and SN50, two specific NF-κB translocation inhibitors, and also found that it could decrease LEF1 expression after HGF treatment. Knockdown of LEF1 by shRNA in MDA-MB-231 cells inhibited tumor invasion induced by HGF treatment. According to IHC staining data, we found that LEF1 is expressed in various cancers. Our study suggests that cross-talk of HGF/Met and Wnt/β-catenin/Tcf/Lef by transcriptional regulation of LEF1 is essential for the invasion-inducing effect of HGF. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10136 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 病理學科所 |
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