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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, p. 529-542Article 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, p. 529-542
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, id: 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: 2018-12-07
In thesis
1. Investigating mechanisms of angiogenesis in health and disease using zebrafish models
Open this publication in new window or tab >>Investigating mechanisms of angiogenesis in health and disease using zebrafish models
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis, the growth of blood vessels from an existing vasculature, can occur by sprouting from preexisting vessels or by vessel splitting (intussusception). Pathological angiogenesis drives choroidal neovascularization (CNV) in age related macular degeneration (AMD) which is commonly restricted under the retinal pigment epithelium (RPE), called occult CNV, but may also involve vessels penetrating through the RPE into the sub-retinal space. Pathological vessels are poorly developed, insufficiently perfused and highly leaky, phenotypes that are considered to drive disease progression and lead to poor prognosis. Currently, a number of anti-angiogenic drugs exists, the majority of which target vascular endothelial factor (VEGF), but although they often are highly beneficial for treating eye diseases in the short-term, they are generally of limited efficacy in other diseases such as cancer, and also have poorer efficacy when used for treatment of eye diseases in the long-term. A better understanding of the mechanisms underlying pathological angiogenesis can generate new targets for treatment leading to development of better drugs for cancer and retinopathies, but perhaps also other angiogenesis-dependent diseases, in the future. In this thesis mechanisms involved in developmental angiogenesis or pathological angiogenesis in the choroid, cornea or melanoma was identified. These findings highlight the need to further elaborate our knowledge related to angiogenesis in different tissues/conditions for a more targeted, and potentially effective treatment of diseases in the future.

In paper I, we for the first time identified the choriocapillaries (CCs) in adult zebrafish and found that occult CNV could be induced by exposing the fish to severe hypoxia. Interestingly, we found that occult CNV relied on intussusception, involving not only de novo generation of intussusceptive pillars but also a previously poorly understood mechanism called pillar splitting. This involved HIF-VEGF-VEGFR2 signaling and evidence that this also occurred in both rats and humans suffering from AMD suggested that the mechanism was conserved and clinically relevant.

In contrast, we found in paper II that the development of CCs in the zebrafish relies on sprouting angiogenesis, involve continuous remodeling, and delayed maturation of the vasculature in 2D. The initial development was found to occur by a unique process of tissuewide synchronized vasculogenesis. As expected, VEGFA via VEGFR2 was also critical for the development of these vessels in the zebrafish embryo, but surprisingly this was independent on hypoxia-inducible factor (HIF)-1.

Inflammatory nuclear factor-kB (NF-kB) signaling is involved in the progression of angiogenesis, but this signaling pathway has mainly been studied in the inflammatory cells and the role of NF-kB in the endothelial cells during angiogenesis is poorly understood. In paper III, we found that blocking NF-kB signaling using a specific IKK2 blocker IMD0354, specifically blocks pathological as well as developmental angiogenesis by targeting endothelial cell NF-kB signaling in the endothelial cells. Using a rat model for suture-induced corneal neovascularization, IMD0354 treatment lead to reduced production of inflammatory C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 5 (CXCL5) and VEGF, and thereby reduced pathological corneal angiogenesis in this model.

Using the zebrafish tumor xenograft model in paper IV, we found an association between Microphthalmia associated transcription factor (MITF) and pigment epithelium derived factor (PEDF), which was involved in pathological tumor angiogenesis and metastasis. Similarly, in paper V we used zebrafish transplantation models to study and investigate the use of biocompatible polymers for the delivery of pro-angiogenic FGF-2 as a potential treatment strategy for ischemic diseases such as myocardial infarction (MI). Conclusively, this thesis provides new insights into diverse fields of angiogenic assays using zebrafish, and reveals new mechanisms of angiogenesis in health and disease. This work will hopefully provide a foundation for further studies into occult CNV related to AMD, a process that has not been possible to study previously in pre-clinical models. In addition, zebrafish xenograft or other transplantation models used in this work will likely be important to study cancer biology and to develop more attractive pharmaceutical preparations based on biocompatible hydrogels formulated as microspheres in the future.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 49
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1646
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-153266 (URN)10.3384/diss.diva-153266 (DOI)9789176851999 (ISBN)
Public defence
2018-12-14, Belladonna, Campus US, Linköping, 13:00 (English)
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Available from: 2018-12-07 Created: 2018-12-07 Last updated: 2019-09-30Bibliographically approved

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