Methylation and Loss of Secreted Frizzled-Related Protein 3 Enhances Melanoma Cell Migration and Invasion

Elin J Ekström,Tommy Andersson,Victoria Sherwood,Neil A Hotchin

doi:10.1371/journal.pone.0018674

Elin J Ekström, Tommy Andersson + Show 2 more

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https://doi.org/10.1371/journal.pone.0018674

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Journal: PloS one	Publication Date: Apr 8, 2011
Citations: 82	License type: CC BY 4.0

Affiliation: Skåne University Hospital, Lund University

Abstract

BackgroundWnt signaling is important in development and can also contribute to the initiation and progression of cancer. The Secreted Frizzled Related Proteins (SFRPs) constitute a family of Wnt modulators, crucial for controlling Wnt signaling. Here we investigate the expression and role of SFRP3 in melanoma.Methodology/Principal FindingsWe show that SFRP3 mRNA is down-regulated in malignant melanoma tumors as compared to normal/benign tissue. Furthermore, we found that SFRP3 expression was lost in the malignant melanoma cell lines, A2058, HTB63 and A375, but not in the non-transformed melanocyte cell line, Hermes 3A. Methylated CpG rich areas were detected in the SFRP3 gene in melanoma cell lines and their SFRP3 expression could be restored using the demethylating agent, 5′aza-deoxycytidine. Addition of recombinant SFRP3 to melanoma cells had no effect on viable cell numbers, but decreased cell migration and invasion. Wnt5a signaling has been shown to increase the migration and invasion of malignant melanoma cells, and high expression of Wnt5a in melanoma tumors has been connected to a poor prognosis. We found that recombinant SFRP3 could inhibit Wnt5a signaling, and that it inhibited melanoma cell migration and invasion in a Wnt5a-dependent manner.Conclusion/SignificanceWe conclude that SFRP3 functions as a melanoma migration and invasion suppressor by interfering with Wnt5a signaling.

Highlights

Wnt signaling is essential in many different biological processes during development and tissue maintenance
Low expression of SFRP3 mRNA was detected in the three melanoma cell lines in contrast to the higher expression in the melanocytes (Figure 1C)
The present finding, that mRNA expression levels are lower in malignant melanoma tissue than in normal skin/benign nevi is in agreement with our observation that the SFRP3 gene is methylated in melanoma cell lines but not in the Hermes 3A melanocyte cell line

Summary

Introduction

Wnt signaling is essential in many different biological processes during development and tissue maintenance. Tight homeostatic control of Wnt signaling is crucial for the organism, as aberrant Wnt signaling can lead to developmental defects and plays important roles in many cancers [1]. There are other putative Wnt receptors such as Ror2 [2,3]. All Wnt-ligands and most of their cognate receptors contain a cysteine-rich domain (CRD), through which their binding is thought to be mediated. Activation of Wnt signaling by proteins such as Wnt3a and Wnt activates canonical signaling that leads to inhibition of b-catenin proteolytic degradation. Wnt signaling is important in development and can contribute to the initiation and progression of cancer. The Secreted Frizzled Related Proteins (SFRPs) constitute a family of Wnt modulators, crucial for controlling Wnt signaling. We investigate the expression and role of SFRP3 in melanoma

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Conclusion