Open Access

FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma

  • Authors:
    • Eva Skarmoutsou
    • Valentina Bevelacqua
    • Fabio D' Amico
    • Angela Russo
    • Demetrios   A. Spandidos
    • Aurora Scalisi
    • Grazia Malaponte
    • Claudio Guarneri
  • View Affiliations

  • Published online on: April 4, 2018     https://doi.org/10.3892/ijmm.2018.3618
  • Pages: 392-404
  • Copyright: © Skarmoutsou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor‑β (TGF‑β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF‑β‑induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno­cytochemical analysis. Gene expression levels were assessed by reverse transcription‑quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ‑secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF‑β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh‑TGF‑β. TGF‑β‑mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh‑TGF‑β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF‑β‑mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability.
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July-2018
Volume 42 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Skarmoutsou E, Bevelacqua V, D' Amico F, Russo A, Spandidos DA, Scalisi A, Malaponte G and Guarneri C: FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma. Int J Mol Med 42: 392-404, 2018.
APA
Skarmoutsou, E., Bevelacqua, V., D' Amico, F., Russo, A., Spandidos, D.A., Scalisi, A. ... Guarneri, C. (2018). FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma. International Journal of Molecular Medicine, 42, 392-404. https://doi.org/10.3892/ijmm.2018.3618
MLA
Skarmoutsou, E., Bevelacqua, V., D' Amico, F., Russo, A., Spandidos, D. A., Scalisi, A., Malaponte, G., Guarneri, C."FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma". International Journal of Molecular Medicine 42.1 (2018): 392-404.
Chicago
Skarmoutsou, E., Bevelacqua, V., D' Amico, F., Russo, A., Spandidos, D. A., Scalisi, A., Malaponte, G., Guarneri, C."FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma". International Journal of Molecular Medicine 42, no. 1 (2018): 392-404. https://doi.org/10.3892/ijmm.2018.3618