- 學位論文
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
若您是本文的作者，可授權文章由華藝線上圖書館中協助推廣。
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。
關鍵字
肝細胞生長因子並列摘要
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.
參考文獻
1. Nakamura, T., Molecular cloning and expression of human hepatocyte growth factor. Nature, 1989. 342: p. 440-443.
2. Trusolino, L. and P.M. Comoglio, Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer, 2002. 2(4): p. 289-300.
3. Stamos, J., et al., Crystal structure of the HGF β-chain in complex with the Sema domain of the Met receptor. EMBO J., 2004. 23: p. 2325-2335.
4. Basilico, C., et al., A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met. J. Biol. Chem., 2008. 283: p. 21267-21277.
5. Ponzetto, C., A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell, 1994. 77: p. 261-271.