FZD4 as a Mediator of ERG Oncogene-Induced WNT Signaling and Epithelial-to-Mesenchymal Transition in Human Prostate Cancer Cells
FZD4 as a Mediator of ERG Oncogene-Induced WNT Signaling and Epithelial-to-Mesenchymal Transition in Human Prostate Cancer Cells
复制标题
DOI：
10.1158/0008-5472.can-10-0244
复制
发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Kallioniemi, Olli
中科院分区：
文献类型：
--
作者：
Gupta, Santosh;Iljin, Kristiina;Kallioniemi, Olli
TMPRSS2-ERG和其他涉及ETS因子和具有强启动子元件的基因融合在前列腺癌中很常见。虽然ERG激活与前列腺癌的侵袭性有关，但ERG介导的肿瘤发生的确切机制和途径仍然知之甚少。在这里，我们发现ERG在VCaP前列腺癌细胞中的敲除导致细胞黏附的激活，导致强烈诱导活化的β(1)-整合素和E-钙粘素的表达以及WNT信号的改变。这些观察结果得到了来自ERG过表达的未转化的前列腺上皮细胞的数据以及来自临床前列腺癌样本的基因表达数据的证实，这些数据都表明ERG与上皮向间充质转化(EMT)之间存在联系。在ERG阳性的前列腺癌中，WNT通路的几个成员表达上调，其中FZD4(FZD4)的过度表达最强，逆转录-聚合酶链式反应和免疫染色都证实了这一点。ERG基因敲除和基因敲除均可调节FZD4的表达水平。FZD4沉默可以通过诱导活跃的β(1)整合素和E-钙粘素表达来模拟ERG基因敲除表型，而FZD4过表达则逆转了ERG基因敲除的表型效应。综上所述，我们的结果为前列腺癌的ERG致癌提供了机制方面的见解，涉及通过FZD4激活WNT信号，导致包括EMT和细胞黏附丧失在内的促癌表型效应。癌症资源；70(17)；6735-45。(C)2010年AACR。
TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active beta(1)-integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active beta(1)-integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion. Cancer Res; 70(17); 6735-45. (C)2010 AACR.