Oncotarget

Research Papers:

A novel tumor suppressor function of Kindlin-3 in solid cancer

Ibtissem Djaafri, Farah Khayati, Suzanne Menashi, Jorg Tost, Marie-Pierre Podgorniak, Aurelie Sadoux, Antoine Daunay, Luis Teixeira, Jean Soulier, Ahmed Idbaih, Niclas Setterblad, Françoise Fauvel, Fabien Calvo, Anne Janin, Celeste Lebbé and Samia Mourah _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2014; 5:8970-8985. https://doi.org/10.18632/oncotarget.2125

Metrics: PDF 4483 views  |   HTML 23713 views  |   ?  


Abstract

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

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 2125