A novel tumor suppressor function of Kindlin-3 in solid cancer
Metrics: PDF 4302 views | HTML 23502 views | ?
Ibtissem Djaafri1,2,*, Farah Khayati1,2,3,*, Suzanne Menashi4, Jorg Tost5,6, Marie-Pierre Podgorniak3, Aurelie Sadoux1,3, Antoine Daunay6, Luis Teixeira7, Jean Soulier2,8, Ahmed Idbaih9,10, Niclas Setterblad1,2, Françoise Fauvel1,2, Fabien Calvo1,2, Anne Janin2,11,12, Celeste Lebbé2,13,14 and Samia Mourah1,2
1 Inserm UMR-S 940 Paris, France
2 Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France
3 AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie-Génétique, Paris, France
4 Université Paris Est Créteil, CNRS-UMR; Créteil, France
5 Laboratory for Epigenetics, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France
6 Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France
7 AP-HP ; Hôpital Saint-Louis, Service d’oncologie médicale, Paris, France
8 Hematology Laboratory APHP, Saint-Louis Hospital, Paris, France
9 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 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, Hôpital Saint-Louis, Laboratoire de Pathologie, Paris, France
13 AP-HP, Hôpital Saint-Louis, Département de Dermatologie, Paris, France
14 Inserm U976, Paris, France
* These Authors contributed equally to this work
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.