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WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1

Oncogene volume 35, pages 12–21 (2016)Cite this article

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Abstract

Glioblastoma is the most aggressive primary brain tumor in adults and due to the invasive nature cannot be completely removed. The WNT inhibitory factor 1 (WIF1), a secreted inhibitor of WNTs, is systematically downregulated in glioblastoma and acts as strong tumor suppressor. The aim of this study was the dissection of WIF1-associated tumor-suppressing effects mediated by canonical and non-canonical WNT signaling. We found that WIF1 besides inhibiting the canonical WNT pathway selectively downregulates the WNT/calcium pathway associated with significant reduction of p38-MAPK (p38-mitogen-activated protein kinase) phosphorylation. Knockdown of WNT5A, the only WNT ligand overexpressed in glioblastoma, phenocopied this inhibitory effect. WIF1 expression inhibited cell migration in vitro and in an orthotopic brain tumor model, in accordance with the known regulatory function of the WNT/Ca2+ pathway on migration and invasion. In search of a mediator for this function differential gene expression profiles of WIF1-expressing cells were performed. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA and key positive regulator of invasion, emerged as the top downregulated gene. Indeed, knockdown of MALAT1 reduced migration in glioblastoma cells, without effect on proliferation. Hence, loss of WIF1 enhances the migratory potential of glioblastoma through WNT5A that activates the WNT/Ca2+ pathway and MALAT1. These data suggest the involvement of canonical and non-canonical WNT pathways in glioblastoma promoting key features associated with this deadly disease, proliferation on one hand and invasion on the other. Successful targeting will require a dual strategy affecting both canonical and non-canonical WNT pathways.

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Acknowledgements

The presented work was supported by the Swiss National Science Foundation (31003A_138116 / 1). The results published here are in part based on data generated by The Cancer TCGA Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/.

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Authors and Affiliations

  1. Neurosurgery (NCH), Lausanne University Hospital (CHUV), Lausanne, Switzerland

    I Vassallo, P Rajakannu, M-F Hamou & M E Hegi

  2. Department of Clinical Neurosciences, Neuroscience Research Center (CRN), Lausanne University Hospital (CHUV), Epalinges, Switzerland

    I Vassallo, P Rajakannu, M-F Hamou & M E Hegi

  3. Department of Neurological Surgery, Baylor College of Medicine, Houston, TX, USA

    P Zinn

  4. Laboratory of Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    M Lai

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Correspondence to M E Hegi.

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Vassallo, I., Zinn, P., Lai, M. et al. WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1. Oncogene 35, 12–21 (2016). https://doi.org/10.1038/onc.2015.61

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