Hypoxia induces a vast array of long noncoding RNAs (lncRNA) in breast cancer cells, but their biological functions remain largely unknown. Here, we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF2), but not HIF1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells in vitro. Gain- and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion in vitro and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis. SIGNIFICANCE: This study reveals the molecular mechanism by which the lncRNA RAB11B-AS1 regulates hypoxia-induced angiogenesis and breast cancer metastasis, and provides new insights into the functional interaction between a lncRNA and tumor microenvironment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/5/964/F1.large.jpg.

中文翻译：

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HIF2诱导的长非编码RNA RAB11B-AS1促进缺氧介导的血管生成和乳腺癌转移。

缺氧可在乳腺癌细胞中诱导大量长链非编码RNA（lncRNA），但其生物学功能仍未知。在这里，我们确定了迄今未表征的缺氧诱导的乳腺癌细胞中的lncRNA RAB11B-AS1。RAB11B-AS1是在人类乳腺癌中上调的天然lncRNA，响应缺氧，其表达是由缺氧诱导因子2（HIF2）诱导的，而不是由HIF1诱导的。RAB11B-AS1通过增加RNA聚合酶II的募集来增强低氧乳腺癌细胞中血管生成因子（包括VEGFA和ANGPTL4）的表达。与增加的血管生成因子一致，来自RAB11B-AS1过量表达的乳腺癌细胞的条件培养基在体外促进人脐静脉内皮细胞的管形成。功能获得和功能丧失研究表明，RAB11B-AS1在体外可增加乳腺癌细胞的迁移和侵袭，并促进肿瘤血管生成和乳腺癌远处转移，而不会影响小鼠的原发性肿瘤生长。综上所述，这些发现揭示了低氧诱导的肿瘤血管生成和乳腺癌转移的基本机制。意义：这项研究揭示了lncRNA RAB11B-AS1调节缺氧诱导的血管生成和乳腺癌转移的分子机制，并为lncRNA与肿瘤微环境之间的功能相互作用提供了新见解。图形摘要：http://cancerres.aacrjournals.org/content/canres/80/5/964/F1.large.jpg。