Abstract

Fascin-1, an actin-bundling protein, plays an important role in cancer cell migration and invasion; however, the underlying mechanism remains unclear. On the basis of a 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cell migration model, it was shown that TPA increased fascin-1 mRNA and protein expression and fascin-1-dependent cell migration. TPA dose- and time-dependently increased PKCδ and STAT3α activation and GSK3β phosphorylation; up-regulated Wnt-1, β-catenin, and STAT3α expression; and increased the nuclear translocation of β-catenin and STAT3α. Rottlerin, a PKCδ inhibitor, abrogated the increases in STAT3α activation and β-catenin and fascin-1 expression. WP1066, a STAT3 inhibitor, suppressed TPA-induced STAT3α DNA binding activity and β-catenin expression. Knockdown of β-catenin attenuated TPA-induced fascin-1 and STAT3α expression as well as cell migration. In addition to MCF-7, migration of Hs578T breast cancer cells was inhibited by silencing fascin-1, β-catenin, and STAT3α expression as well. TPA also induced Wnt-1 expression and secretion, and blocking Wnt-1 signaling abrogated β-catenin induction. DHA pretreatment attenuated TPA-induced cell migration, PKCδ and STAT3α activation, GSK3β phosphorylation, and Wnt-1, β-catenin, STAT3α, and fascin-1 expression. Our results demonstrated that TPA-induced migration is likely associated with the PKCδ and Wnt-1 pathways, which lead to STAT3α activation, GSK3β inactivation, and β-catenin increase and up-regulation of fascin-1 expression. Moreover, the anti-metastatic potential of DHA is partly attributed to its suppression of TPA-activated PKCδ and Wnt-1 signaling.

Highlights

  • Metastasis is the most common cause of poor prognosis and worse survival rates in cancer patients

  • To verify that fascin-1 plays an important role in breast cancer cell migration, MCF-7 cells were treated with tetradecanoylphorbol 13-acetate (TPA) and Western blotting and the wound healing assay were performed

  • These findings indicated that induction of fascin-1 is important in TPA-induced MCF-7 cell migration and that the anti-migration effect of Docosahexaenoic acid (DHA) is likely associated with the suppression of this actin filament bundling protein

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Summary

Introduction

Metastasis is the most common cause of poor prognosis and worse survival rates in cancer patients. A meta-analysis reported that fascin, an actin-bundling protein, is consistently associated with increased risk of metastasis and mortality in numerous carcinomas, such as the gastric, colorectal, and breast cancers [1]. The fascin protein family consists of three subtypes: fascin-1, fascin-2, and fascin-3 [2]. Fascin-1, is expressed in various cell types in normal tissues. Fascin expression is induced by a variety of cytokines such as www.impactjournals.com/oncotarget interleukin-6 (IL-6) and oncostatin M via transactivation of signal transducers and activators of transcription 3 (STAT3) in breast cancer cells [6]. Transcription factors such as nuclear factor κB (NFκB) and hypoxia-inducible factor promote fascin gene transcription [7, 8]

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