Regulation of amphiregulin gene expression by β-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system.
Regulation of amphiregulin gene expression by β-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system.
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DOI：
10.1371/journal.pone.0052711
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Avila MA
中科院分区：
文献类型：
--
作者：
Latasa MU;Salis F;Urtasun R;Garcia-Irigoyen O;Elizalde M;Uriarte I;Santamaria M;Feo F;Pascale RM;Prieto J;Berasain C;Avila MA
肝细胞癌是最常见的肝脏肿瘤，也是一种治疗手段有限的致命性疾病。细胞信号通路的失调是肿瘤发生的共同因素，包括肝癌的发生。表皮生长因子受体(EGFR)信号系统在肝细胞癌中通常被激活，目前正被评估为联合治疗的治疗靶点。我们和其他人已经确定了EGFR配体两端调节蛋白(AR)在肝癌细胞的增殖、存活和耐药性中的核心作用。AR在肝癌组织和细胞中的表达经常上调，其机制尚不完全清楚。在这里，我们确定β-连环蛋白信号通路是导致人肝癌细胞AR基因转录激活的一种新机制。β-连环蛋白信号的激活或T41aβ-连环蛋白活性突变体的表达，导致AR表达的诱导涉及其近端启动子中的三个特定的β-连环蛋白-Tcf反应元件。我们证明，表达T41aβ-连环蛋白活性突变体的肝癌细胞表现出增强的增殖，这在一定程度上依赖于AR的表达和EGFR信号。我们还在这里展示了EGFR系统与成纤维细胞生长因子19(FGF19)的新的相互作用。FGF19是最近发现的一个在肝癌发生过程中的驱动基因，也是肝癌和结肠癌细胞中β-连环蛋白信号的激活子。我们发现成纤维细胞生长因子19通过β-连环蛋白途径诱导人肝癌细胞AR基因的表达。重要的是，AR上调和EGFR信号转导参与了FGF19诱导细胞周期蛋白D1和细胞增殖的过程。最后，我们证明了FGF19和AR在人肝细胞癌组织中的表达呈正相关，因此在临床样本中支持我们的实验观察。这些发现表明，AR/EGFR系统是肝癌细胞中涉及β-连环蛋白信号转导的FGF19反应的关键介质，并提示联合靶向FGF19和AR/EGFR可能会提高治疗效果。
Hepatocellular carcinoma (HCC) is the most prevalent liver tumor and a deadly disease with limited therapeutic options. Dysregulation of cell signaling pathways is a common denominator in tumorigenesis, including hepatocarcinogenesis. The epidermal growth factor receptor (EGFR) signaling system is commonly activated in HCC, and is currently being evaluated as a therapeutic target in combination therapies. We and others have identified a central role for the EGFR ligand amphiregulin (AR) in the proliferation, survival and drug resistance of HCC cells. AR expression is frequently up-regulated in HCC tissues and cells through mechanisms not completely known. Here we identify the β-catenin signaling pathway as a novel mechanism leading to transcriptional activation of the AR gene in human HCC cells. Activation of β-catenin signaling, or expression of the T41A β-catenin active mutant, led to the induction of AR expression involving three specific β-catenin-Tcf responsive elements in its proximal promoter. We demonstrate that HCC cells expressing the T41A β-catenin active mutant show enhanced proliferation that is dependent in part on AR expression and EGFR signaling. We also demonstrate here a novel cross-talk of the EGFR system with fibroblast growth factor 19 (FGF19). FGF19 is a recently identified driver gene in hepatocarcinogenesis and an activator of β-catenin signaling in HCC and colon cancer cells. We show that FGF19 induced AR gene expression through the β-catenin pathway in human HCC cells. Importantly, AR up-regulation and EGFR signaling participated in the induction of cyclin D1 and cell proliferation elicited by FGF19. Finally, we demonstrate a positive correlation between FGF19 and AR expression in human HCC tissues, therefore supporting in clinical samples our experimental observations. These findings identify the AR/EGFR system as a key mediator of FGF19 responses in HCC cells involving β-catenin signaling, and suggest that combined targeting of FGF19 and AR/EGFR may enhance therapeutic efficacy.
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影响因子：
25.7
作者：
Blivet-Van Eggelpoel, Marie-Jose;Chettouh, Hamza;Desbois-Mouthon, Christele
通讯作者：
Desbois-Mouthon, Christele
影响因子：
4
作者：
Bade, Lindsey K.;Goldberg, Jodi E.;Schwertfeger, Kathryn L.
通讯作者：
Schwertfeger, Kathryn L.
影响因子：
8
作者：
Desbois-Mouthon, C;Cadoret, A;Capeau, J
通讯作者：
Capeau, J
肝癌中表皮生长因子受体（EGFR）串扰。
影响因子：
5.2
作者：
Berasain C;Ujue Latasa M;Urtasun R;Goñi S;Elizalde M;Garcia-Irigoyen O;Azcona M;Prieto J;Avila MA
通讯作者：
Avila MA
影响因子：
5.6
作者：
Baillo, Andrea;Giroux, Craig;Ethier, Stephen P.
通讯作者：
Ethier, Stephen P.