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Fucoidan inhibits epithelial-to-mesenchymal transition via regulation of the HIF-1? pathway in mammary cancer cells under hypoxia.

ABSTRACT: This study examined the effects of fucoidan on epithelial-to-mesenchymal transition (EMT) in a human triple-negative breast cancer (TNBC) cell line in a hypoxic microenvironment. Transwell and wound-healing assays were performed to analyze the invasion and migration of MDA-MB-231 human mammary cancer cells, respectively. The expression levels of EMT markers and hypoxia-inducible factor-1? (HIF-1?) were detected through western blotting. Under hypoxia, fucoidan treatment inhibited proliferation of breast cancer cells. Fucoidan also suppressed the invasion and migration of MDA-MB-231 cells. Western blotting revealed that fucoidan treatment significantly reduced the protein expression levels of HIF-1? and HIF-1 target genes. Furthermore, the nuclear translocation and activity of HIF-1? were reduced. Fucoidan treatment significantly downregulated the expression levels of mesenchymal markers (N-cadherin and vimentin), but upregulated the expression levels of the epithelial markers zonula occludens-1 and E-cadherin. In addition, overexpression of HIF1-? protected cells from fucoidan-mediated suppression of migration and invasion. These data suggested that fucoidan may inhibit EMT in human TNBC cells via downregulation of the HIF1-? signaling pathway.

SUBMITTER: Li W

PROVIDER: S-EPMC6539587 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Fucoidan inhibits epithelial-to-mesenchymal transition via regulation of the HIF-1α pathway in mammary cancer cells under hypoxia.

Li Weiwei W Xue Dingshan D Xue Meilan M Zhao Jinglan J Liang Hui H Liu Ying Y Sun Ting T

Oncology letters 20190425 1

This study examined the effects of fucoidan on epithelial-to-mesenchymal transition (EMT) in a human triple-negative breast cancer (TNBC) cell line in a hypoxic microenvironment. Transwell and wound-healing assays were performed to analyze the invasion and migration of MDA-MB-231 human mammary cancer cells, respectively. The expression levels of EMT markers and hypoxia-inducible factor-1α (HIF-1α) were detected through western blotting. Under hypoxia, fucoidan treatment inhibited proliferation o ...[more]

PMID: 31289504

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Project description:BackgroundTumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pathways of individual TME are extensively studied, evidence showing interaction and crosstalk between hypoxia and inflammation remain unclear. Thus, we examined whether interferon (IFN) could modulate both inflammatory and hypoxic responses under normoxia and its relation with cancer development.MethodsIFN was used to induce inflammation response and HIF-1α expression in various cancer cell lines. Corresponding signaling pathways were then analyzed by a combination of pharmacological inhibitors, immunoblotting, GST-Raf pull-down assays, dominant-negative and short-hairpin RNA-mediated knockdown approaches. Specifically, roles of functional HIF-1α in the IFN-induced epithelial-mesenchymal transition (EMT) and other tumorigenic propensities were examined by knockdown, pharmacological inhibition, luciferase reporter, clonogenic, anchorage-independent growth, wound-healing, vasculogenic mimicry, invasion and sphere-formation assays as well as cellular morphology observation.ResultsWe showed for the first time that IFN induced functional HIF-1α expression in a time- and dose- dependent manner in various cancer cell lines under both hypoxic and normoxic conditions, and then leading to an activated HIF-1α pathway in an IFN-mediated pro-inflammatory TME. IFN regulates anti-apoptosis activity, cellular metastasis, EMT and vasculogenic mimicry by a novel mechanism through mainly the activation of PI3K/AKT/mTOR axis. Subsequently, pharmacological and genetic modulations of HIF-1α, JAK, PI3K/AKT/mTOR or p38 pathways efficiently abrogate above IFN-induced tumorigenic propensities. Moreover, HIF-1α is required for the IFN-induced invasiveness, tumorigenesis and vasculogenic mimicry. Further supports for the HIF-1α-dependent tumorigenesis were obtained from results of xenograft mouse model and sphere-formation assay.ConclusionsOur mechanistic study showed an induction of HIF-1α and EMT ability in an IFN-mediated inflammatory TME and thus demonstrating a novel interaction between inflammatory and hypoxic TMEs. Moreover, targeting HIF-1α may be a potential target for inhibiting tumor tumorigenesis and EMT by decreasing cancer cells wound healing and anchorage-independent colony growth. Our results also lead to rationale guidance for developing new therapeutic strategies to prevent relapse via targeting TME-providing IFN signaling and HIF-1α programming.

Dataset Information

Fucoidan inhibits epithelial-to-mesenchymal transition via regulation of the HIF-1? pathway in mammary cancer cells under hypoxia.

Publications

Fucoidan inhibits epithelial-to-mesenchymal transition via regulation of the HIF-1α pathway in mammary cancer cells under hypoxia.

Similar Datasets

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