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Oncotarget. 2014 Oct 15;5(19):8970-85.

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

Author information

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.

PMID:
25344860
PMCID:
PMC4253411
DOI:
10.18632/oncotarget.2125
[Indexed for MEDLINE]
Free PMC Article

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