1. A novel tumor suppressor function of Kindlin-3 in solid cancer
- Author
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Luis Augusto Teixeira, Marie-Pierre Podgorniak, Françoise Fauvel, Jean Soulier, Céleste Lebbé, Anne Janin, Samia Mourah, Fabien Calvo, Suzanne Menashi, Ibtissem Djaafri, Jörg Tost, Ahmed Idbaih, Niclas Setterblad, Aurélie Sadoux, Antoine Daunay, and Farah Khayati
- Subjects
Talin ,Integrins ,Platelet aggregation ,Metastatic phenotype ,Kindlin-3 ,Invasion/Migration ,Metastasis ,law.invention ,Mice ,0302 clinical medicine ,law ,Medicine ,Genes, Tumor Suppressor ,Tumor suppressor gene ,Neoplasm Metastasis ,Phosphorylation ,RNA, Small Interfering ,Melanoma ,0303 health sciences ,Hematology ,Metastasis formation ,Integrin beta3 ,Neoplasm Proteins ,3. Good health ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Azacitidine ,Heterografts ,Female ,RNA Interference ,Research Paper ,medicine.medical_specialty ,Solid cancer ,Breast Neoplasms ,Decitabine ,03 medical and health sciences ,Cell Line, Tumor ,Internal medicine ,Cell Adhesion ,Animals ,Humans ,metastasis ,Neoplasm Invasiveness ,RNA, Messenger ,Cell Proliferation ,030304 developmental biology ,business.industry ,Membrane Proteins ,DNA Methylation ,medicine.disease ,Immunology ,Cancer research ,Suppressor ,business ,Neoplasm Transplantation - Abstract
// Ibtissem Djaafri 1,2,* , Farah Khayati 1,2,3,* , Suzanne Menashi 4 , Jorg Tost 5,6 , Marie-Pierre Podgorniak 3 , Aurelie Sadoux 1,3 , Antoine Daunay 6 , Luis Teixeira 7 , Jean Soulier 2,8 , Ahmed Idbaih 9,10 , Niclas Setterblad 1,2 , Francoise Fauvel 1,2 , Fabien Calvo 1,2 , Anne Janin 2,11,12 , Celeste Lebbe 2,13,14 and Samia Mourah 1,2 1 Inserm UMR-S 940 Paris, France 2 Institute of Hematology (IUH), U niversite Paris-Diderot, Sorbonne Paris Cite, Paris, France 3 AP-HP, Hopital Saint-Louis, Laboratoire de Pharmacologie-Genetique, Paris, France 4 Universite Paris Est Creteil, CNRS-UMR; Creteil, France 5 Laboratory for Epigenetics, Centre National de Genotypage, CEA-Institut de Genomique, Evry, France 6 Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France 7 AP-HP ; Hopital Saint-Louis, Service d’oncologie medicale, Paris, France 8 Hematology Laboratory APHP, Saint-Louis Hospital, Paris, France 9 AP-HP, Groupe Hospitalier Pitie-Salpetriere, Service de Neurologie 2-Mazarin, Paris, France 10 Inserm U 975, Paris, 75013 France, CNRS, UMR, Paris, France 11 Inserm, U728, Paris, France 12 AP-HP, Hopital Saint-Louis, Laboratoire de Pathologie, Paris, France 13 AP-HP, Hopital Saint-Louis, Departement de Dermatologie, Paris, France 14 Inserm U976, Paris, France * These Authors contributed equally to this work Correspondence: Samia Mourah, email: // Keywords : Tumor suppressor gene, Kindlin-3, Invasion/Migration, metastasis, Integrins Received : May 26, 2014 Accepted : June 18, 2014 Published : June 20, 2014 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 Kindin-3 which can influence integrins targeted therapies development.
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- 2014