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Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer

Authors Fuady J, Bordoli M, Abreu-Rodríguez I, Kristiansen G, Hoogewijs D, Stiehl D, Wenger R

Received 22 December 2013

Accepted for publication 4 February 2014

Published 31 March 2014 Volume 2014:2 Pages 23—33

DOI https://doi.org/10.2147/HP.S54404

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Jerry H Fuady,1,* Mattia R Bordoli,1,* Irene Abreu-Rodríguez,1,* Glen Kristiansen,2 David Hoogewijs,1,** Daniel P Stiehl,1,** Roland H Wenger1,**

1Institute of Physiology and Zurich Center for Human Physiology, University of Zurich, Zurich, Switzerland; 2University Hospital Bonn, Institute of Pathology, Bonn, Germany

*,**These authors contributed equally to this work

Abstract: Hypoxia and the hypoxia-inducible factor (HIF) signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2), which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2α-dependent manner. HIF-2-driven regulation of the WISP2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2α, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low-invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2α silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2α tumor levels with prolonged overall survival of patients with breast cancer.

Keywords: invasion, metastasis, motility, oxygen, tumor, transcriptional regulation

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