Myoferlin is a novel exosomal protein and functional regulator of cancer-derived exosomes.
Myoferlin is a novel exosomal protein and functional regulator of cancer-derived exosomes.
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DOI：
10.18632/oncotarget.13276
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发表时间：
2016-12-13
期刊：
影响因子：
--
通讯作者：
Turtoi A
中科院分区：
文献类型：
--
作者：
Blomme A;Fahmy K;Peulen O;Costanza B;Fontaine M;Struman I;Baiwir D;de Pauw E;Thiry M;Bellahcène A;Castronovo V;Turtoi A
外泌体是参与细胞间蛋白质、代谢物和核酸交换的通讯介质。最近的研究表明，外泌体具有独特的蛋白质组学组成，与细胞蛋白质组学组成不同。然而，决定外泌体蛋白质组含量的机制仍然不清楚。在目前的研究中，我们采用超微结构的方法来验证一种新的外泌体蛋白肌钙蛋白。这是一种含有多个c2结构域的蛋白，以其在胞吞作用和囊泡融合生物学中的保守生理功能而闻名。新出现的研究表明，myoferlin在癌症中经常过度表达，促进癌细胞迁移和侵袭。我们的数据通过显示肌钙素是来自不同乳腺癌和胰腺癌细胞系的癌细胞衍生外泌体的一般成分来扩展这些发现。利用蛋白质组学分析，我们首次证明了癌细胞中的肌钙素耗竭会导致外泌体蛋白负荷的显著调节。这种肌钙蛋白缺失的外泌体也存在功能缺陷，其向人内皮细胞（HUVEC）转移核酸的能力降低。除此之外，肌钙蛋白缺失的癌症外泌体诱导HUVEC迁移和增殖的能力也显著降低。目前的研究强调肌钙蛋白是外泌体生物学中的一个新的功能参与者，需要新的策略来靶向人类癌症中的这个新兴的癌基因。
Exosomes are communication mediators participating in the intercellular exchange of proteins, metabolites and nucleic acids. Recent studies have demonstrated that exosomes are characterized by a unique proteomic composition that is distinct from the cellular one. The mechanisms responsible for determining the proteome content of the exosomes remain however obscure. In the current study we employ ultrastructural approach to validate a novel exosomal protein myoferlin. This is a multiple C2-domain containing protein, known for its conserved physiological function in endocytosis and vesicle fusion biology. Emerging studies demonstrate that myoferlin is frequently overexpressed in cancer, where it promotes cancer cell migration and invasion. Our data expand these findings by showing that myoferlin is a general component of cancer cell derived exosomes from different breast and pancreatic cancer cell lines. Using proteomic analysis, we demonstrate for the first time that myoferlin depletion in cancer cells leads to a significantly modulated exosomal protein load. Such myoferlin-depleted exosomes were also functionally deficient as shown by their reduced capacity to transfer nucleic acids to human endothelial cells (HUVEC). Beyond this, myoferlin-depleted cancer exosomes also had a significantly reduced ability to induce migration and proliferation of HUVEC. The present study highlights myoferlin as a new functional player in exosome biology, calling for novel strategies to target this emerging oncogene in human cancer.