Abstract
BackgroundMuch effort has been devoted to determining how metastatic cells and microenvironment reciprocally interact. However, the role of biological stimuli of microenvironment in controlling molecular events in bone metastasis from breast carcinoma for mesenchymal-epithelial transition (MET) is largely unknown. The purpose of the present paper was to clarify (1) the influence of hepatocyte-growth factor (HGF) and transforming growth factorβ1 (TGFβ1) on the phenotype of bone-metastatic 1833 and parental MDA-MB231 cells; (2) the hierarchic response of Twist and Snail controlled by Wwox co-factor, that might be critical for the control of 1833-adhesive properties via E-cadherin.MethodsWe studied under HGF and TGFβ1 the gene profiles—responsible for epithelial-mesenchymal transition (EMT), versus the revertant MET phenotype—making the correspondence with 1833 morphology and the relation to HGF-dependent control of TGFβ1 signalling. In particular, the activation of Twist program and the underlying molecular mechanisms were investigated, considering the role of endogenous and exogenous Wwox with siRNAWWOX and the expression vector transfection, to clarify whether Twist affected E-cadherin transactivation through a network of transcription factors and regulators.ResultsHGF and TGFβ1 oppositely affected the expression of Wwox in 1833 cells. Under HGF, endogenous Wwox decreased concomitant with Twist access to nuclei and its phosphorylation via PI3K/Akt pathway. Twist activated by HGF did not influence the gene profile through an E-box mechanism, but participated in the interplay of PPARγ/Ets1/NF-kB-transcription factors, triggering E-cadherin transactivation. Altogether, HGF conferred MET phenotype to 1833 cells, even if this was transient since followed by TGFβ1-signalling activation. TGFβ1 induced Snail in both the cell lines, with E-cadherin down-regulation only in 1833 cells because in MDA-MB231 cells E-cadherin was practically absent. Exogenous Wwox activated metastatic HIF-1, with Twist as co-factor.ConclusionsHGF and TGFβ1 of bone-metastasis microenvironment acted co-ordinately, influencing non redundant pathways regulated by Twist program or Snail-transcription factor, with reversible MET switch. This process implicated different roles for Wwox in the various steps of the metastatic process including colonization, with microenvironmental/exogenous Wwox that activated HIF-1, important for E-cadherin expression. Interfering with the Twist program by targeting the pre-metastatic niche stimuli could be an effective anti-bone metastasis therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0389-y) contains supplementary material, which is available to authorized users.
Highlights
Much effort has been devoted to determining how metastatic cells and microenvironmentT reciprocally interact
R factorβ1 (TGFβ1) on the phenotype of bone-metastatic 1833 and parental MDA-MB231 cells; (2) the hierarchic A response of Twist and Snail controlled by WW-domain containing oxidoreductase (Wwox) co-factor, that might be critical for the control of 1833-adhesive properties via E-cadherin
WWOX expression vector from breast cancer depended on Twist and Snail, we (e.v.) reduced Twist-luciferase activity in untransfected, evaluated their expression and intracellular localization in response to hepatocyte-growth factor (HGF) and transforming growthR factorβ1 (TGFβ1), two typical stimuli of bone microenvironment [1, 2, 4, 25]
Summary
Much effort has been devoted to determining how metastatic cells and microenvironmentT reciprocally interact. R factorβ (TGFβ1) on the phenotype of bone-metastatic 1833 and parental MDA-MB231 cells; (2) the hierarchic A response of Twist and Snail controlled by Wwox co-factor, that might be critical for the control of 1833-adhesive properties via E-cadherin. The disparate nature of stimuli in metastasis micro- ylation and relocation to the nuclei, Wwox receives and environment determines epithelial-mesenchymal tran- integrates cell-surface signals like TGFβ [22]. Nuclear sition (EMT), or more likely the molecular events that Wwox may either enhance or inhibit transcription-factor influence the reversion to MET phenotype [1,2,3,4]. The engineered loss of the EMT transcription factors evidences the importance of MET in lung metastasis from breast cancer, identifying Id1 and 3 as fundamental genes, and transforming-growth factor β (TGFβ)-Id1 signalling that opposes Twist [12]. EMT seems a transient process, present at least only at the sequestering [22, 24]
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