Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition
Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition
复制标题
DOI：
10.1038/sj.onc.1210546
复制
发表时间：
2007-11-22
期刊：
影响因子：
8
通讯作者：
Larue, L.
中科院分区：
文献类型：
--
作者：
Julien, S.;Puig, I.;Larue, L.
癌症进展与上皮特征的丧失以及肿瘤细胞获得间质特征和侵袭特性有关。细胞与细胞接触的丧失可能是。上皮间质转化 (EMT) 的第一步，涉及细胞间粘附分子 E-钙粘蛋白的功能失活。转录因子 Snail 对 E-钙粘蛋白表达的抑制是上皮表型丧失过程中的一个中心事件。 Akt 激酶激活在人类癌症中很常见，Akt 调节包括 EMT 在内的各种细胞机制。在这里，我们表明 Snail 激活和随后的 E-钙粘蛋白抑制可能依赖于 AKT 介导的核因子 kappa B (NF-kappa B) 激活，并且 NF-kappa B 诱导 Snail 表达。 NF-kappa B 亚基 p65 的表达足以诱导 EMT，从而在 EMT 过程中验证了该信号模块。 NF-kappa B 通路激活与多种人类肿瘤类型的肿瘤进展和转移相关； E-钙粘蛋白充当转移抑制蛋白。因此，这种在 EMT 过程中连接 AKT、NF-kappa B、Snail 和 E-cadherin 的信号传导和转录网络是抗转移治疗的潜在靶点。
Carcinoma progression is associated with the loss of epithelial features, and the acquisition of mesenchymal characteristics and invasive properties by tumour cells. The loss of cell-cell contacts may be the. first step of the epithelium mesenchyme transition (EMT) and involves the functional inactivation of the cell-cell adhesion molecule E-cadherin. Repression of E-cadherin expression by the transcription factor Snail is a central event during the loss of epithelial phenotype. Akt kinase activation is frequent in human carcinomas, and Akt regulates various cellular mechanisms including EMT. Here, we show that Snail activation and consequent repression of E- cadherin may depend on AKT-mediated nuclear factor-kappa B (NF-kappa B) activation, and that NF-kappa B induces Snail expression. Expression of the NF-kappa B subunit p65 is suficient for EMT induction, validating this signalling module during EMT. NF-kappa B pathway activation is associated with tumour progression and metastasis of several human tumour types; E-cadherin acts as a metastasis suppressor protein. Thus, this signalling and transcriptional network linking AKT, NF-kappa B, Snail and E-cadherin during EMT is a potential target for antimetastatic therapeutics.