EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination.
EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination.
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DOI：
10.1038/onc.2014.200
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发表时间：
2015-05-14
期刊：
影响因子：
8
通讯作者：
del Peso L
中科院分区：
文献类型：
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作者：
Gómez-Maldonado L;Tiana M;Roche O;Prado-Cabrero A;Jensen L;Fernandez-Barral A;Guijarro-Muñoz I;Favaro E;Moreno-Bueno G;Sanz L;Aragones J;Harris A;Volpert O;Jimenez B;del Peso L
实体瘤中缺氧区域的存在是患者预后的不良预后因素。在这里，我们表明，缺氧诱导Ephrin-A3的表达通过一种新的缺氧诱导因子（HIF）介导的机制。在低氧条件下，编码EFNA 3的mRNA水平保持相对稳定，但HIF驱动了EFNA 3基因座的未知长非编码（Inc）RNA的表达，这些IncRNA导致Ephrin-A3蛋白的积累。肝配蛋白是一种细胞表面蛋白，通过调节细胞粘附和排斥来调节多种生物过程。越来越多的证据表明，肝配蛋白功能失调在肿瘤生物学的多个方面。我们证明了Ephrin-A3和新型EFNA 3 lncRNA的持续表达增加了人乳腺癌细胞的转移潜力，这可能是通过增加肿瘤细胞从血管外渗到周围组织的能力。一致的是，我们发现乳腺癌患者中EFNA 3高表达与较短的无转移生存期之间存在强相关性。总之，我们的研究结果表明，缺氧可能有助于乳腺癌的转移扩散，通过HIF介导的诱导EFNA 3 lncRNA和随后的Ephrin-A3蛋白积累。
The presence of hypoxic regions in solid tumors is an adverse prognostic factor for patient outcome. Here, we show that hypoxia induces the expression of Ephrin-A3 through a novel hypoxia-inducible factor (HIF)-mediated mechanism. In response to hypoxia, the coding EFNA3 mRNA levels remained relatively stable, but HIFs drove the expression of previously unknown long noncoding (Inc) RNAs from EFNA3 locus and these IncRNA caused Ephrin-A3 protein accumulation. Ephrins are cell surface proteins that regulate diverse biological processes by modulating cellular adhesion and repulsion. Mounting evidence implicates deregulated ephrin function in multiple aspects of tumor biology. We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. Taken together, our results suggest that hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction of EFNA3 lncRNAs and subsequent Ephrin-A3 protein accumulation.