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Neoplasia. 2014 Jun;16(6):529-42. doi: 10.1016/j.neo.2014.06.001. Epub 2014 Jul 13.

Regulatory and functional connection of microphthalmia-associated transcription factor and anti-metastatic pigment epithelium derived factor in melanoma.

Author information

1
Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
2
Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1UL, United Kingdom.
3
Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
4
Division of Cardiovascular Medicine, Department of Medical and Health sciences, Linköping University, Linköping, Sweden.
5
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Centre for Gene Regulation & Expression, College of Life Sciences, Universtity of Dundee, Dundee DD1 5EH, United Kingdom.
6
Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Tumor Suppressor Signaling Networks Laboratory, UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
7
Department of Pathology, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid, Spain; Instituto de Investigación I+12, Madrid, Spain.
8
Department of Pathology, Capio-Fundación Jimenez Díaz, Madrid, Spain.
9
INSERM U895 Team 1 and Department of Dermatology, CHU Nice, France.
10
Institute de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
11
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
12
Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Instituto de Investigación I+12, Madrid, Spain. Electronic address: bjimenez@iib.uam.es.

Abstract

Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.

KEYWORDS:

Abbreviations; BRAF; CM; MITF; NRAS; OIS; PEDF; RGP; VGP; VM; cutaneous metastasis of melanoma; heterogeneous nuclear RNA; hnRNA; microphthalmia-associated transcription factor; neuroblastoma RAS viral (v-ras) oncogene homolog; oncogene induced senescence; pigment epithelium-derived factor; radial growth phase of melanoma; v-raf murine sarcoma viral oncogene homolog B; vertical growth phase of melanoma; visceral metastasis of melanoma

PMID:
25030625
PMCID:
PMC4198745
DOI:
10.1016/j.neo.2014.06.001
[Indexed for MEDLINE]
Free PMC Article

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