期刊
ONCOTARGET
卷 5, 期 19, 页码 8970-8985出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2125
关键词
Tumor suppressor gene; Kindlin-3; Invasion/Migration; metastasis; Integrins
资金
- Institut National de la Sante et de la Recherche Medicale
- La Ligue Nationale Contre le Cancer
- La Societe Francaise de Dermatologie, Universites Paris Diderot
- Canceropole d'Ile de France
- Fondation ARC pour la Recherche sur le Cancer
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 beta 3-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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