Selective extracellular vesicle exclusion of miR-142-3p by oral cancer cells promotes both internal and extracellular malignant phenotypes.
Selective extracellular vesicle exclusion of miR-142-3p by oral cancer cells promotes both internal and extracellular malignant phenotypes.
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DOI：
10.18632/oncotarget.14862
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发表时间：
2017-02-28
期刊：
影响因子：
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通讯作者：
Garnis C
中科院分区：
文献类型：
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作者：
Dickman CT;Lawson J;Jabalee J;MacLellan SA;LePard NE;Bennewith KL;Garnis C
将小分子因子（包括miRNA）包装到小细胞外囊泡（SEV）中可能有助于恶性表型并促进癌细胞和肿瘤基质之间的通讯。一些miRNA被封闭在SEV中的过程是选择性的而不是不加选择的，选择部分由特定的miRNA序列控制。在此，我们描述了在一组口腔异型增生和口腔鳞状细胞癌细胞系中通过SEV选择性包装和去除四种miRNA（miR-142- 3 p、miR-150- 5 p、miR-451 a和miR-223- 3 p）。外泌体输出蛋白Rab 27 A的抑制增加了这些miRNA候选物的细胞内浓度，并防止它们通过SEV被排除。发现细胞内miR-142- 3 p的增加专门针对TGFBR 1，导致供体细胞中TGFBR 1表达减少，并减少生长和集落形成等恶性特征。相反，发现miR-142- 3 p通过供体细胞SEV的分泌增加和受体内皮细胞的摄取减少TGFBR 1活性，并在体外和体内引起这些细胞中的促肿瘤变化。
Packaging of small molecular factors, including miRNAs, into small extracellular vesicles (SEVs) may contribute to malignant phenotypes and facilitate communication between cancer cells and tumor stroma. The process by which some miRNAs are enclosed in SEVs is selective rather than indiscriminate, with selection in part governed by specific miRNA sequences. Herein, we describe the selective packaging and removal via SEVs of four miRNAs (miR-142-3p, miR-150-5p, miR-451a, and miR-223-3p) in a panel of oral dysplasia and oral squamous cell carcinoma cell lines. Inhibition of exosome export protein Rab27A increased intracellular concentration of these miRNA candidates and prevented their exclusion via SEVs. Increased intracellular miR-142-3p specifically was found to target TGFBR1, causing a decrease in TGFBR1 expression in donor cells and a reduction of malignant features such as growth and colony formation. Conversely, increased excretion of miR-142-3p via donor cell SEVs and uptake by recipient endothelial cells was found to reduce TGFBR1 activity and cause tumor-promoting changes in these cells in vitro and in vivo.