title: 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.
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.
authors.affiliation: INSERM U753, Institut Gustave Roussy, Villejuif, France.
authors.forename: I
authors.initials: I
authors.lastname: Akalay
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: T Z
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Sante), Luxembourg, Luxembourg.
authors.forename: B
authors.initials: B
authors.lastname: Janji
authors.affiliation: INSERM U753, Institut Gustave Roussy, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Mami-Chouaib
authors.affiliation: Laboratoire de Recherche Translationnelle-module d'histocytopathologie et Centre de Ressources Biologiques, Institut de cancérologie Gustave-Roussy, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Charpy
authors.affiliation: Laboratoire de Recherche Translationnelle-module d'histocytopathologie et Centre de Ressources Biologiques, Institut de cancérologie Gustave-Roussy, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Vielh
authors.affiliation: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938 and Université Pierre et Marie Curie, Paris, France.
authors.forename: A K
authors.initials: AK
authors.lastname: Larsen
authors.affiliation: 1] Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore [2] Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore [3] Department of Biochemistry, National University of Singapore, Singapore, Singapore.
authors.forename: J P
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938 and Université Pierre et Marie Curie, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Sabbah
authors.affiliation: INSERM U753, Institut Gustave Roussy, Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology*; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D012334:RNA, Neoplasm / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D060449:Wnt Signaling Pathway
chemical_list: D055511:CCN Intercellular Signaling Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C413323:CCN5 protein, human; C000715467:KLF4 protein, human; C549242:MIRN7-1 microRNA, human