Toufaily Chirine, Charfi Cyndia, Annabi Bayader, Annabi Borhane
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre de Recherche BIOMED, Université du Québec à Montreal, Quebec, Canada.
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre de Recherche BIOMED, Université du Québec à Montreal, Quebec, Canada. ; Département de Physiologie, Faculté de Médecine, Université de Montreal, Montreal, Canada.
Cancer Growth Metastasis. 2014 Dec 8;7:43-51. doi: 10.4137/CGM.S18581. eCollection 2014.
Caveolae are specialized cell membrane invaginations known to regulate several cancer cell functions and oncogenic signaling pathways. Among other caveolar proteins, they are characterized by the presence of proteins of the cavin family. In this study, we assessed the impact of cavin-1, cavin-2, and cavin-3 on cell migration in a human HT-1080 fibrosarcoma model. We found that all cavin-1, -2 and -3 transcripts were expressed and that treatment with phorbol 12-myristate 13-acetate (PMA), which is known to prime cell migration and proliferation, specifically upregulated cavin-3 gene and protein expression. PMA also triggered matrix metalloproteinase (MMP)-9 secretion, but reduced the global cell migration index. Overexpression of recombinant forms of the three cavins demonstrated that only cavin-3 was able to reduce basal cell migration, and this anti-migratory effect was potentiated by PMA. Interestingly, cavin-3 overexpression inhibited PMA-induced MMP-9, while cavin-3 gene silencing led to an increase in MMP-9 gene expression and secretion. Furthermore, recombinant cavin-3 significantly prevented PMA-mediated dephosphorylation of AKT, a crucial regulator in MMP-9 transcription. In conclusion, our results demonstrate that cellular cavin-3 expression may repress MMP-9 transcriptional regulation in part through AKT. We suggest that the balance in cavin-3-to-MMP-9 expression regulates the extent of extracellular matrix degradation, confirming the tumor-suppressive role of cavin-3 in controlling the invasive potential of human fibrosarcoma cells.
小窝是一种特殊的细胞膜内陷结构,已知其可调节多种癌细胞功能和致癌信号通路。除其他小窝蛋白外,它们的特征是存在小窝蛋白家族的蛋白质。在本研究中,我们评估了小窝蛋白-1、小窝蛋白-2和小窝蛋白-3对人HT-1080纤维肉瘤模型中细胞迁移的影响。我们发现所有小窝蛋白-1、-2和-3转录本均有表达,并且用佛波酯12-肉豆蔻酸酯13-乙酸酯(PMA)处理,已知其可引发细胞迁移和增殖,特异性地上调了小窝蛋白-3基因和蛋白表达。PMA还触发了基质金属蛋白酶(MMP)-9的分泌,但降低了整体细胞迁移指数。三种小窝蛋白重组形式的过表达表明,只有小窝蛋白-3能够降低基础细胞迁移,并且这种抗迁移作用被PMA增强。有趣的是,小窝蛋白-3过表达抑制了PMA诱导的MMP-9,而小窝蛋白-3基因沉默导致MMP-9基因表达和分泌增加。此外,重组小窝蛋白-3显著阻止了PMA介导的AKT去磷酸化,AKT是MMP-9转录中的关键调节因子。总之,我们的结果表明,细胞中小窝蛋白-3的表达可能部分通过AKT抑制MMP-9转录调控。我们认为小窝蛋白-3与MMP-9表达的平衡调节细胞外基质降解的程度,证实了小窝蛋白-3在控制人纤维肉瘤细胞侵袭潜能方面的肿瘤抑制作用。