title: A novel tumor suppressor function of Kindlin-3 in solid cancer.
abstract: Kindlin-3 (FERMT-3) is known to be central in hemostasis and thrombosis control and its deficiency disrupts platelet aggregation and causes Leukocyte Adhesion Deficiency disease. Here we report that Kindlin-3 has a tumor suppressive role in solid cancer. Our present genetic and functional data show that Kindlin-3 is downregulated in several solid tumors by a mechanism involving gene hypermethylation and deletions. In vivo experiments demonstrated that Kindlin-3 knockdown in 2 tumor cell models (breast cancer and melanoma) markedly increases metastasis formation, in accord with the in vitro increase of tumor cell malignant properties. The metastatic phenotype was supported by a mechanism involving alteration in β3-integrin activation including decreased phosphorylation, interaction with talin and the internalization of its active form leading to less cell attachment and more migration/invasion. These data uncover a novel and unexpected tumor suppressor role of Kindlin-3 which can influence integrins targeted therapies development.
authors.affiliation: Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Djaafri
authors.affiliation: Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie-Génétique, Paris, France.
authors.forename: Farah
authors.initials: F
authors.lastname: Khayati
authors.affiliation: Université Paris Est Créteil, CNRS-UMR; Créteil, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Menashi
authors.affiliation: Laboratory for Epigenetics, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France. Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France.
authors.forename: Jorg
authors.initials: J
authors.lastname: Tost
authors.affiliation: AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie-Génétique, Paris, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Podgorniak
authors.affiliation: Inserm UMR-S 940 Paris, France. AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie-Génétique, Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Sadoux
authors.affiliation: Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Daunay
authors.affiliation: AP-HP, Hôpital Saint-Louis, Service d'oncologie médicale, Paris, France.
authors.forename: Luis
authors.initials: L
authors.lastname: Teixeira
authors.affiliation: Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. Hematology Laboratory APHP, Saint-Louis Hospital, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France. Inserm U 975, Paris, 75013 France, CNRS, UMR, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Niclas
authors.initials: N
authors.lastname: Setterblad
authors.affiliation: Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Fauvel
authors.affiliation: Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.affiliation: Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. Inserm, U728, Paris, France. AP-HP, Hôpital Saint-Louis, Laboratoire de Pathologie, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.affiliation: Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. AP-HP, Hôpital Saint-Louis, Département de Dermatologie, Paris, France. Inserm U976, Paris, France.
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbé
authors.affiliation: Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D016608:Talin / Q000235:genetics
chemical_list: C477322:FERMT3 protein, human; D039661:Integrin beta3; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016608:Talin; D000077209:Decitabine; D001374:Azacitidine