Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/β-catenin signaling pathway
Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/β-catenin signaling pathway
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DOI：
10.1016/j.canlet.2015.05.023
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发表时间：
2015-08-28
期刊：
影响因子：
9.7
通讯作者：
Unno, Michiaki
中科院分区：
文献类型：
--
作者：
Douchi, Daisuke;Ohtsuka, Hideo;Unno, Michiaki
经典的Wnt/β-catenin信号通路已被证明促进上皮-间质转化（EMT），这是多个胚胎发育过程和癌症进展中的关键过程。我们最近提供的证据表明，富含亮氨酸的重复flightless-1相互作用蛋白1（LRFIP 1）促进癌症转移和侵袭。在本研究中，我们确定了LRFIP 1靶向的信号传导元件，以促进胰腺癌和肺癌中的EMT。LRRFIP 1沉默逆转EMT，如通过增加E-钙粘蛋白（上皮标记物）的表达和减少波形蛋白（间充质标记物）的表达所示。LRFIP 1沉默上调P-连环蛋白的磷酸化，并通过靶向P-连环蛋白破坏复合物降低其核定位。在LRFIP 1沉默的癌细胞中，质膜组分中的β-连环蛋白和E-钙粘蛋白的表达增加，并且迁移和侵袭能力被强烈抑制。此外，该蛋白在从胰腺癌患者收集的恶性组织的侵袭前沿高度表达。因此，我们的数据有力地表明，LRFIP 1在癌细胞的侵袭中起着重要作用。我们的数据提供了实验证据，表明LRFIP 1是人类癌症靶向治疗的有吸引力的候选者。(C)2015爱思唯尔爱尔兰有限公司版权所有。
The canonical Wnt/beta-catenin signaling pathway has been shown to promote the epithelial-mesenchymal transition (EMT), which is a crucial process in multiple embryonic developmental processes and the progression of carcinomas. We recently provided evidence that leucine-rich repeat flightless-1-interacting protein 1 (LRRFIP1) promotes cancer metastasis and invasion. In the present study, we identified the signaling elements targeted by LRRFIP1 for promotion of the EMT in pancreatic and lung cancer. LRRFIP1 silencing reversed the EMT, as shown by increased expression of E-cadherin (an epithelial marker) and decreased expression of vimentin (a mesenchymal marker). Silencing of LRRFIP1 up-regulated phosphorylation of P-catenin and decreased its nuclear localization by targeting the p-catenin destruction complex. The expression of p-catenin and E-cadherin in the plasma membrane fraction was increased in LRRFIP1 silenced cancer cells, and the migration and invasion capabilities were strongly inhibited. In addition, this protein was highly expressed at the invasion front of malignant tissue collected from pancreatic cancer patients. Consequently, our data strongly suggested that LRRFIP1 played an important role in the invasion of carcinoma cells. Our data provide experimental evidence that LRRFIP1 is an attractive candidate for targeted therapy in human cancers. (C) 2015 Elsevier Ireland Ltd. All rights reserved.