Dataset Information

Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin ?2?1-contacting-mediated activation of Wnt-?-catenin pathway.

ABSTRACT: BACKGROUND:Integrin-mediated platelet-tumor cell contacting plays an important role in promoting epithelial-mesenchymal transition (EMT) transformation of tumor cells and cancer metastasis, but whether it occurs in breast cancer cells is not completely clear. OBJECTIVE:The purpose of this study was to investigate the role of integrin ?2?1 in platelet contacting to human breast cancer cell line MCF-7 and its effect on the EMT and the invasion of MCF-7 cells. METHODS:Human platelets were activated by thrombin, and separated into pellets and releasates before the co-incubation with MCF-7 cells. Cell invasion was evaluated by transwell assay. The surface integrins on pellets and MCF-7 cells were inhibited by antibodies. The effect of integrin ?2?1 on Wnt-?-catenin pathway was assessed by integrin ?2?1-silencing and Wnt-?-catenin inhibitor XAV. The therapeutic effect of integrin ?2?1-silencing was confirmed in the xenograft mouse model. RESULTS:Pellets promote the invasion and EMT of MCF-7 cells via direct contacting of surface integrin ?2?1. The integrin ?2?1 contacting activates Wnt-?-catenin pathway and promotes the expression of EMT proteins in MCF-7 cells. The activated Wnt-?-catenin pathway also promotes the autocrine of TGF-?1 in MCF-7 cells. Both Wnt-?-catenin and TGF-?1/pSmad3 pathways promote the expression of EMT proteins. Integrin ?2?1-silencing inhibits breast cancer metastasis in vivo. CONCLUSIONS:The direct interaction between platelets and tumor cells exerts its pro-metastatic function via surface integrin ?2?1 contacting and Wnt-?-catenin activation. Integrin ?2?1-silencing has the potential effect of inhibiting breast cancer metastasis.

SUBMITTER: Zuo XX

PROVIDER: S-EPMC6836423 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin α2β1-contacting-mediated activation of Wnt-β-catenin pathway.

Zuo Xiao-Xiao XX Yang Ya Y Zhang Yue Y Zhang Zhi-Gang ZG Wang Xiao-Fei XF Shi Yong-Gang YG

Cell communication and signaling : CCS 20191107 1

<h4>Background</h4>Integrin-mediated platelet-tumor cell contacting plays an important role in promoting epithelial-mesenchymal transition (EMT) transformation of tumor cells and cancer metastasis, but whether it occurs in breast cancer cells is not completely clear.<h4>Objective</h4>The purpose of this study was to investigate the role of integrin α2β1 in platelet contacting to human breast cancer cell line MCF-7 and its effect on the EMT and the invasion of MCF-7 cells.<h4>Methods</h4>Human pl ...[more]

PMID: 31699102

Similar Datasets

Project description:The acquisition of integrin-directed metastasis-associated (ID-MA) phenotypes by Triple-Negative Breast Cancer (TNBC) cells is caused by an upregulation of the Wnt-beta-catenin pathway (WP). We reported that WP is one of the salient genetic features of TNBC. RAC-GTPases, small G-proteins which transduce signals from cell surface proteins including integrins, have been implicated in tumorigenesis and metastasis by their role in essential cellular functions like motility. The collective percentage of alteration(s) in RAC1 in ER+ve BC was lower as compared to ER-ve BC (35% vs 57%) (brca/tcga/pub2015). High expression of RAC1 was associated with poor outcome for RFS with HR=1.48 [CI: 1.15-1.9] p=0.0019 in the Hungarian ER-veBC cohort. Here we examined how WP signals are transduced via RAC1 in the context of ID-MA phenotypes in TNBC. Using pharmacological agents (sulindac sulfide), genetic tools (beta-catenin siRNA), WP modulators (Wnt-C59, XAV939), RAC1 inhibitors (NSC23766, W56) and WP stimulations (LWnt3ACM, Wnt3A recombinant) in a panel of 6-7 TNBC cell lines, we studied fibronectin-directed (1) migration, (2) matrigel invasion, (3) RAC1 and Cdc42 activation, (4) actin dynamics (confocal microscopy) and (5) podia-parameters. An attenuation of WP, which (a) decreased cellular levels of beta-catenin, as well as its nuclear active-form, (b) decreased fibronectin-induced migration, (c) decreased invasion, (d) altered actin dynamics and (e) decreased podia-parameters was successful in blocking fibronectin-mediated RAC1/Cdc42 activity. Both Wnt-antagonists and RAC1 inhibitors blocked fibronectin-induced RAC1 activation and inhibited the fibronectin-induced ID-MA phenotypes following specific WP stimulation by LWnt3ACM as well as Wnt3A recombinant protein. To test a direct involvement of RAC1-activation in WP-mediated ID-MA phenotypes, we stimulated brain-metastasis specific MDA-MB231BR cells with LWnt3ACM. LWnt3ACM-stimulated fibronectin-directed migration was blocked by RAC1 inhibition in MDA-MB231BR cells. In the light of our previous report that WP upregulation causes ID-MA phenotypes in TNBC tumor cells, here we provide the first mechanism based evidence to demonstrate that WP upregulation signals ID-MA tumor cell phenotypes in a RAC1-GTPase dependent manner involving exchange-factors like TIAM1 and VAV2. Our study demonstrates for the first time that beta-catenin-RAC1 cascade signals integrin-directed metastasis-associated tumor cell phenotypes in TNBC.

Project description:It has been suggested that drug tolerance represents a form of learning and memory, but this has not been experimentally established at the molecular level. We show that a component of alcohol molecular tolerance (channel internalization) from rat hippocampal neurons requires protein synthesis, in common with other forms of learning and memory. We identify ?-catenin as a primary necessary protein. Alcohol increases ?-catenin, and blocking accumulation of ?-catenin blocks alcohol-induced internalization in these neurons. In transfected HEK293 cells, suppression of Wnt/?-catenin signaling blocks ethanol-induced internalization. Conversely, activation of Wnt/?-catenin reduces BK current density. A point mutation in a putative glycogen synthase kinase phosophorylation site within the S10 region of BK blocks internalization, suggesting that Wnt/?-catenin directly regulates alcohol-induced BK internalization via glycogen synthase kinase phosphorylation. These findings establish de novo protein synthesis and Wnt/?-catenin signaling as critical in mediating a persistent form of BK molecular alcohol tolerance establishing a commonality with other forms of long-term plasticity.Alcohol tolerance is a key step toward escalating alcohol consumption and subsequent dependence. Our research aims to make significant contributions toward novel, therapeutic approaches to prevent and treat alcohol misuse by understanding the molecular mechanisms of alcohol tolerance. In our current study, we identify the role of a key regulatory pathway in alcohol-induced persistent molecular changes within the hippocampus. The canonical Wnt/?-catenin pathway regulates BK channel surface expression in a protein synthesis-dependent manner reminiscent of other forms of long-term hippocampal neuronal adaptations. This unique insight opens the possibility of using clinically tested drugs, targeting the Wnt/?-catenin pathway, for the novel use of preventing and treating alcohol dependency.

Dataset Information

Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin ?2?1-contacting-mediated activation of Wnt-?-catenin pathway.

Publications

Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin α2β1-contacting-mediated activation of Wnt-β-catenin pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure