A pan-cancer analysis of secreted Frizzled-related proteins: re-examining their proposed tumour suppressive function

Krista Marie Vincent,Lynne-Marie Postovit

doi:10.1038/srep42719

Krista Marie Vincent, Lynne-Marie Postovit

Open Access

https://doi.org/10.1038/srep42719

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Journal: Scientific Reports	Publication Date: Feb 20, 2017
Citations: 43	License type: open-access

Affiliation: University of Alberta, Western University

Abstract

Secreted frizzled-related proteins (SFRPs), containing five family members (SFRPs 1–5) are putative extracellular Wnt inhibitors. Given their abilities to inhibit Wnt signalling, as well as the loss of SFRP1 in many cancers, this family is generally considered to be tumour suppressive. In this study we analyzed gene expression, promoter methylation and survival data from over 8000 tumour and normal samples from 29 cancers in order to map the context-specific associations of SFRPs 1–5 with patient survival, gene silencing and gene expression signatures. We show that only SFRP1 associates consistently with tumour suppressive functions, and that SFRP2 and SFRP4 typically associate with a poor prognosis concomitant with the expression of genes associated with epithelial-to-mesenchymal transition. Moreover, our results indicate that while SFRP1 is lost in cancer cells via the process of DNA methylation, SFRP2 and 4 are likely derived from the tumour stroma, and thus tend to increase in tumours as compared to normal tissues. This in-depth analysis highlights the need to study each SFRP as a separate entity and suggests that SFRP2 and SFRP4 should be approached as complex matricellular proteins with functions that extend far beyond their putative Wnt antagonistic ability.

Highlights

Secreted Frizzled-related proteins (SFRPs) were initially described as tumour suppressor genes when SFRP1 was found to be downregulated by loss of heterozygosity or promoter methylation in breast and colorectal cancer cell lines[1,2]
We found that SFRP2 and 4 expression is tightly correlated to stromal content, and forms part of a common epithelial-to-mesenchymal transition (EMT) gene program that is expressed in a multitude of different cancers
We observed select consistent cancer-specific or gene-specific effects: For example, high expression of any SFRP was associated with poor prognosis in stomach cancer; and high expression of SFRP4 only associated with poor outcomes (p < 0.05)

Summary

Introduction

Secreted Frizzled-related proteins (SFRPs) were initially described as tumour suppressor genes when SFRP1 was found to be downregulated by loss of heterozygosity or promoter methylation in breast and colorectal cancer cell lines[1,2] Given their crucial role in Wnt signalling, and in development, the SFRP gene family was quickly recognized for its potential to modulate tumourigenic behaviour. Through stabilizing beta-catenin mutations) is recognized to contribute to tumourigenesis[6] Due to their ability to antagonize Wnt signalling, and their frequent epigenetic silencing, SFRPs were initially designated as tumour suppressor genes and many studies have gone on to support this proposed functional role We found that SFRP1 is the only family member whose expression is consistently decreased in primary cancer samples as compared to associated normal tissues This loss of SFRP1 expression correlates with gene promoter methylation. We found that SFRP2 and 4 expression is tightly correlated to stromal content, and forms part of a common epithelial-to-mesenchymal transition (EMT) gene program that is expressed in a multitude of different cancers

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