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Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression

Oncogene volume 34, pages 2261–2271 (2015)Cite this article

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Abstract

The molecular basis for the resistance of tumor cells to cell-mediated cytotoxicity remains poorly understood and thus poses a major challenge for cancer immunotherapy. The present study was designed to determine whether the WNT1-inducible signaling pathway protein 2 (WISP2, also referred to as CCN5), a key regulator of tumor cell plasticity, interferes with tumor susceptibility to cytotoxic T-lymphocyte (CTL)-mediated lysis. We found that silencing WISP2 signaling in human breast adenocarcinoma MCF7 cells impairs CTL-mediated cell killing by a mechanism involving stem cell marker Kruppel-like factor-4 (KLF-4) induction and microRNA-7 (miR-7) downregulation. Inhibition of transforming growth factor beta (TGF-β) signaling using the A83-01 inhibitor in MCF7-shWISP2 cells resulted in a significant reversal of the epithelial-to-mesenchymal-transitioned (EMT) phenotype, the expression of KLF-4 and a partial recovery of target susceptibility to CTLs. More importantly, we showed that silencing KLF-4 was accompanied by a reduction in MCF7-shWISP2 resistance to CTLs. Using human breast cancer tissues, we demonstrated the coexpression of KLF-4 with EMT markers and TGF-β pathway signaling components. More importantly, we found that KLF-4 expression was accompanied by miR-7 inhibition, which is partly responsible for impairing CTL-mediated lysis. Thus, our data indicate that WISP2 has a role in regulating tumor cell susceptibility through EMT by inducing the TGF-β signaling pathway, KLF-4 expression and miR-7 inhibition. These studies indicate for the first time that WISP2 acts as an activator of CTL-induced killing and suggests that the loss of its function promotes evasion of immunosurveillance and the ensuing progression of the tumor.

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Acknowledgements

This work was supported by grants from INSERM, la Ligue Nationale Contre le Cancer, l’Association de Recherche sur le Cancer, A*STAR Institute of Molecular Cell Biology, Cancer Science Institute National University of Singapore core grants, CRP-Santé and Fondation Cancer, Luxembourg.

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Authors and Affiliations

  1. INSERM U753, Institut Gustave Roussy, Villejuif, France

    I Akalay, F Mami-Chouaib & S Chouaib

  2. Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore

    T Z Tan, P Kumar & J P Thiery

  3. Department of Oncology, Laboratory of Experimental Hemato-Oncology, Public Research Center for Health (CRP-Sante), Luxembourg, Luxembourg

    B Janji

  4. Laboratoire de Recherche Translationnelle-module d’histocytopathologie et Centre de Ressources Biologiques, Institut de cancérologie Gustave-Roussy, Villejuif, France

    C Charpy & P Vielh

  5. Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938 and Université Pierre et Marie Curie, Paris, France

    A K Larsen & M Sabbah

  6. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    J P Thiery

  7. Department of Biochemistry, National University of Singapore, Singapore, Singapore

    J P Thiery

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  1. I Akalay
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Correspondence to S Chouaib.

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Akalay, I., Tan, T., Kumar, P. et al. Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene 34, 2261–2271 (2015). https://doi.org/10.1038/onc.2014.151

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