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; Samia Mourah

doi:10.18632/oncotarget.2125

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

Oncotarget. 2014 Oct 15;5(19):8970-85. doi: 10.18632/oncotarget.2125.

Authors

Affiliations

¹ Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
² 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.
³ Université Paris Est Créteil, CNRS-UMR; Créteil, France.
⁴ Laboratory for Epigenetics, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France. Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France.
⁵ AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie-Génétique, Paris, France.
⁶ Inserm UMR-S 940 Paris, France. AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie-Génétique, Paris, France.
⁷ Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France.
⁸ AP-HP, Hôpital Saint-Louis, Service d'oncologie médicale, Paris, France.
⁹ Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. Hematology Laboratory APHP, Saint-Louis Hospital, Paris, France.
¹⁰ AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France. Inserm U 975, Paris, 75013 France, CNRS, UMR, Paris, France.
¹¹ 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.
¹² 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azacitidine / analogs & derivatives
Azacitidine / pharmacology
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / pathology*
Cell Adhesion / genetics
Cell Line, Tumor
Cell Proliferation / genetics
DNA Methylation
Decitabine
Female
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor*
Heterografts
Humans
Integrin beta3 / metabolism
Melanoma / drug therapy
Melanoma / genetics
Melanoma / pathology*
Membrane Proteins / biosynthesis
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Neoplasm Invasiveness / genetics
Neoplasm Metastasis / genetics
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Neoplasm Transplantation
Phosphorylation
RNA Interference
RNA, Messenger / biosynthesis
RNA, Small Interfering
Talin / genetics

Substances

FERMT3 protein, human
Integrin beta3
Membrane Proteins
Neoplasm Proteins
RNA, Messenger
RNA, Small Interfering
Talin
Decitabine
Azacitidine