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Regulatory and Functional Connection of Microphthalmia-Associated Transcription Factor and Anti-Metastatic Pigment Epithelium Derived Factor in Melanoma
University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain .
University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain Kings Coll London, England .
University of Autonoma Madrid, Spain CSIC UAM Madrid, Spain University of Glasgow, Scotland .
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
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2014 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 6, 529-542 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Neoplasia , 2014. Vol. 16, no 6, 529-542 p.
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-110497DOI: 10.1016/j.neo.2014.06.001ISI: 000340553600007PubMedID: 25030625OAI: oai:DiVA.org:liu-110497DiVA: diva2:746840
Note

Funding Agencies|Ministerio de Ciencia y Competitividad of Spain [SAF-2010-19256, SAF-2011-24225, SAF-2012-32117, FIS 11/02568, RD09/0076/0101, PT13/0010/0012, PI12/01552]; LiU-Cancer; Svenska Sallskapet for Medicinsk Forskning; Ake Wibergs Stiftelse; Goesta Fraenkels Stifelse; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer

Available from: 2014-09-15 Created: 2014-09-12 Last updated: 2017-12-05

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Ali, ZaheerJensen, Lasse

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