E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression
E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression
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DOI：
10.1038/onc.2011.6
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发表时间：
2011-06-01
期刊：
影响因子：
8
通讯作者：
Leung, P. C. K.
中科院分区：
文献类型：
--
作者：
Lau, M-T;Klausen, C.;Leung, P. C. K.
E-钙粘蛋白是一种细胞间粘附蛋白和肿瘤抑制因子，在许多恶性肿瘤中沉默。E-钙粘蛋白被认为通过拮抗β-连环蛋白信号传导来抑制肿瘤细胞生长。然而，E-cadherin在卵巢癌进展中的作用仍然存在争议。在这项研究中，我们发现，E-cadherin的损失诱导卵巢癌细胞的生长和组成型激活的磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通过抑制磷酸酶和张力蛋白同源物（PTEN）的转录通过下调早期生长反应基因1（Egr 1）。此外，免疫荧光显微镜和T细胞因子启动子/荧光素酶报告基因检测表明，E-钙粘蛋白的丢失与增强的细胞核β-连环蛋白信号传导有关。PI 3 K/Akt信号传导的组成性激活通过使糖原合成酶激酶-3 β失活而增强核β-连环蛋白信号传导，表明PI 3 K/Akt和β-连环蛋白信号传导途径之间的串扰。最后，我们发现E-钙粘蛋白负调控肿瘤细胞生长，部分是通过β-连环蛋白介导的Egr 1调节正调控PTEN表达，从而影响PI 3 K/Akt信号传导。总之，内源性E-钙粘蛋白通过拮抗β-连环蛋白-Egr 1介导的对PTEN表达的抑制来抑制PI 3 K/Akt信号传导。因此，E-钙粘蛋白本身的缺失可能通过其对PTEN的作用而导致PI 3 K/Akt信号传导失调，或者它可能加剧由于过表达、突变和/或扩增而发生的PI 3 K/Akt信号传导的频繁激活。Oncogene（2011）30，2753-2766; doi：10.1038/onc.2011.6; 2011年2月7日在线发表
E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing beta-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear beta-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear beta-catenin signaling by inactivating glycogen synthase kinase-3 beta indicating cross-talk between the PI3K/Akt and beta-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via beta-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing beta-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification. Oncogene (2011) 30, 2753-2766; doi: 10.1038/onc.2011.6; published online 7 February 2011