Djaafri Ibtissem, Khayati Farah, Menashi Suzanne, Tost Jorg, Podgorniak Marie-Pierre, Sadoux Aurelie, Daunay Antoine, Teixeira Luis, Soulier Jean, Idbaih Ahmed, Setterblad Niclas, Fauvel Françoise, Calvo Fabien, Janin Anne, Lebbé Celeste, Mourah Samia
Inserm UMR-S 940 Paris, France. Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
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.
Oncotarget. 2014 Oct 15;5(19):8970-85. doi: 10.18632/oncotarget.2125.
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.
已知Kindlin-3（FERMT-3）在止血和血栓形成控制中起核心作用，其缺乏会破坏血小板聚集并导致白细胞粘附缺陷病。在此我们报告，Kindlin-3在实体癌中具有肿瘤抑制作用。我们目前的基因和功能数据表明，Kindlin-3在几种实体瘤中通过涉及基因高甲基化和缺失的机制而下调。体内实验表明，在2种肿瘤细胞模型（乳腺癌和黑色素瘤）中敲低Kindlin-3会显著增加转移灶的形成，这与肿瘤细胞恶性特性在体外的增加一致。转移表型由一种机制支持，该机制涉及β3整合素激活的改变，包括磷酸化减少、与踝蛋白的相互作用以及其活性形式的内化，导致细胞附着减少和更多的迁移/侵袭。这些数据揭示了Kindlin-3一种新的、意想不到的肿瘤抑制作用，这可能会影响整合素靶向治疗的发展。
