Gap junctions modulate glioma invasion by direct transfer of microRNA.
Gap junctions modulate glioma invasion by direct transfer of microRNA.
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DOI：
10.18632/oncotarget.3904
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
Naus CC
中科院分区：
文献类型：
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作者：
Hong X;Sin WC;Harris AL;Naus CC
高级别胶质瘤的侵袭性是治疗后存活率低的主要原因。胶质瘤细胞与周围星形胶质细胞之间的相互作用对肿瘤的侵袭至关重要。在此背景下，我们研究了缝隙连接介导的miRNA转移的作用。通过用缝隙连接抑制物siRNAs和显性负连接蛋白突变体操纵缝隙连接，我们在体外跨井侵袭实验中表明，功能性胶质瘤-胶质瘤缝隙连接抑制胶质瘤的侵袭，而胶质瘤-星形胶质细胞和星形胶质细胞-星形胶质细胞缝隙连接促进它的侵袭。在证明胶质瘤-星形胶质细胞缝隙连接对microRNA具有渗透性之后，我们比较了星形胶质细胞与胶质瘤细胞共培养前后的microRNA谱，确定了特定的microRNA可以通过缝隙连接从胶质瘤细胞转移到星形胶质细胞。进一步的分析表明，miR-5096从胶质瘤细胞转移到星形胶质细胞是通过缝隙连接；这种转移在一定程度上是亲侵袭效应的原因。我们的结果证实了胶质瘤-星形胶质细胞缝隙连接介导的microRNA信号在调节胶质瘤侵袭行为中的作用，并且星形胶质细胞之间的缝隙连接偶联放大了促侵袭信号。我们的发现揭示了基于通过操纵microRNA和缝隙连接通道活性来消除肿瘤细胞对基质细胞的改变的治疗干预的可能性。
The invasiveness of high-grade glioma is the primary reason for poor survival following treatment. Interaction between glioma cells and surrounding astrocytes are crucial to invasion. We investigated the role of gap junction mediated miRNA transfer in this context. By manipulating gap junctions with a gap junction inhibitor, siRNAs, and a dominant negative connexin mutant, we showed that functional glioma-glioma gap junctions suppress glioma invasion while glioma-astrocyte and astrocyte-astrocyte gap junctions promote it in an in vitro transwell invasion assay. After demonstrating that glioma-astrocyte gap junctions are permeable to microRNA, we compared the microRNA profiles of astrocytes before and after co-culture with glioma cells, identifying specific microRNAs as candidates for transfer through gap junctions from glioma cells to astrocytes. Further analysis showed that transfer of miR-5096 from glioma cells to astrocytes is through gap junctions; this transfer is responsible, in part, for the pro-invasive effect. Our results establish a role for glioma-astrocyte gap junction mediated microRNA signaling in modulation of glioma invasive behavior, and that gap junction coupling among astrocytes magnifies the pro-invasive signaling. Our findings reveal the potential for therapeutic interventions based on abolishing alteration of stromal cells by tumor cells via manipulation of microRNA and gap junction channel activity.