title: ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis.
abstract: Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ΔNp63α, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ΔNp63α-expressing cells within a TGFβ-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ΔNp63α-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ΔNp63α repressed miR-527 and miR-665, leading to the upregulation of two TGFβ effectors, SMAD4 and TβRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound-healing response. We show that ΔNp63α-mediated repression of miR-527/665 controls a TGFβ-dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236-51. ©2016 AACR.
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Lidia
authors.initials: L
authors.lastname: Rodriguez Calleja
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Jacques
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France. Nantes University Hospital, Nantes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Tellez Gabriel
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale, Université Claude Bernard Lyon 1, Paris, France.
authors.forename: Debashish
authors.initials: D
authors.lastname: Sahay
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France. Nantes University Hospital, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Perrot
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Charrier
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Regis
authors.initials: R
authors.lastname: Brion
authors.affiliation: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Verrecchia
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France. Nantes University Hospital, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts. Benjamin.ory@univ-nantes.fr LELLISEN@mgh.harvard.edu.
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.affiliation: INSERM, UMR-S 957, Nantes, Equipe labellisée LIGUE 2012, France. Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, Rue Gaston Veil, Nantes, France. Benjamin.ory@univ-nantes.fr LELLISEN@mgh.harvard.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; D020033:Protein Isoforms; D012333:RNA, Messenger; C115051:TP63 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins