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Abstract
Epithelial–mesenchymal transition (EMT) is a crucial step in tumor progression and has an important role during cancer invasion and metastasis. Although fucosyltransferase IV (FUT4) has been implicated in the modulation of cell migration, invasion and cancer metastasis, its role during EMT is unclear. This study explores the molecular mechanisms of the involvement of FUT4 in EMT in breast cancer cells. Breast cancer cell lines display increased expression of FUT4, which is accompanied by enhanced appearance of the mesenchymal phenotype and which can be reversed by knockdown of endogenous FUT4. Moreover, FUT4 induced activation of phosphatidylinositol 3-kinase (PI3K)/Akt, and inactivation of GSK3β and nuclear translocation of NF-κB, resulting in increased Snail and MMP-9 expression and greater cell motility. Taken together, these findings indicate that FUT4 has a role in EMT through activation of the PI3K/Akt and NF-κB signaling systems, which induce the key mediators Snail and MMP-9 and facilitate the acquisition of a mesenchymal phenotype. Our findings support the possibility that FUT4 is a novel regulator of EMT in breast cancer cells and a promising target for cancer therapy.
Highlights
During the multiple step of Epithelial–mesenchymal transition (EMT), epithelial cells lose numerous epithelial characteristics to assume the properties of mesenchymal cells
We found that FUT4 had a critical role in the mitogen-activated protein kinases (MAPKs) pathway by mediating EGF-induced NF-kB activation and increasing expression of MMP-12.25 Given that FUT4 may have an important role in tumor metastasis, we were prompted in this study to explore its role in the induction of EMT in breast cancer cells
We propose that FUT4, via activation of NF-kB and phosphatidylinositol 3-kinase (PI3K)/Akt-GSK3b signaling, enhances the expression of Snail, leading to acquisition of the mesenchymal phenotype in breast cancer cells
Summary
During the multiple step of EMT, epithelial cells lose numerous epithelial characteristics to assume the properties of mesenchymal cells. The EMT-related signaling pathways in the tumor microenvironment include TGF-b, NF-kB, Wnt, Notch and others.[4,5] Several transcription factors have been implicated in the transcriptional repression of E-cadherin, including the Snail family of zinc-finger transcription factors (Snail, Slug and Smuc), the two-handed zinc-finger members of the dEF1 family (ZEB1/dEF1 and ZEB-2/SIP1) and the basic helix–loop–helix factors Twist.[6,7] All of these transcription factors have been recognized as having a critical role in cell survival, differentiation and metastasis Among these factors, NF-kB can directly activate the expression of potent inducers of EMT, including Snail and ZEB factors.[8] It has shown that NF-kB suppresses the expression of epitheliumspecific gene E-cadherin and induces the expression of the mesenchymal-specific gene vimentin. Our study supports the possibility that FUT4 is a novel regulator of EMT in breast cancer cells and is a promising target for cancer therapy
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