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HIF2-Induced Long Noncoding RNA RAB11B-AS1 Promotes Hypoxia-Mediated Angiogenesis and Breast Cancer Metastasis.

ABSTRACT: 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.

SUBMITTER: Niu Y

PROVIDER: S-EPMC7056556 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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HIF2-Induced Long Noncoding RNA RAB11B-AS1 Promotes Hypoxia-Mediated Angiogenesis and Breast Cancer Metastasis.

Niu Yanling Y Bao Lei L Chen Yan Y Wang Chenliang C Luo Maowu M Zhang Bo B Zhou Mi M Wang Jennifer E JE Fang Yisheng V YV Kumar Ashwani A Xing Chao C Wang Yingfei Y Luo Weibo W

Cancer research 20200103 5

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 ANGPTL ...[more]

PMID: 31900259

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Project description:OBJECTIVES:The long-noncoding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes in glioblastoma (GBM) tissues. However, the expression pattern and biological function of lncRNAs remain largely unknown. Here, for the first time, the effects of lncRNA lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) on GBM progression both in vitro and in vivo are investigated. MATERIALS AND METHODS:Expression profiles of LEF1-AS1 in GBM specimens were investigated by bioinformatics analyses. LEF1-AS1 expression in GBM tissues was detected using a quantitative polymerase chain reaction. LEF1-AS1 expression was inhibited by transfecting the LEF1-AS1-specific small interfering RNAs (siRNAs) and stable cell lines established were inhibited by transfecting si-LEF1-AS1 viruses. The Cell Counting Kit-8, ethynyl deoxyuridine, and colony formation assay were used to examine proliferation function. The flow cytometry detected cell-cycle change and apoptosis. Migration effects were detected by a Transwell assay. The tumor xenografts and immunohistochemistry were performed to evaluate tumor growth in vivo. RESULTS:In this study, LEF1-AS1 expression was found significantly upregulated in GBM specimens compared with normal tissues. The 5-year overall survival in GBM patients from The Cancer Genome Atlas with high expression of LEF1-AS1 was inferior to that with low expression. It was confirmed that expression of LEF1-AS1 was higher in GBM tissues than normal ones. Knockdown of LEF1-AS1 significantly inhibited the malignancy of GBM cells, including proliferation and invasion, and promoted cell apoptosis. The result of Western blot assays indicated that knockdown of LEF1-AS1-mediated tumor suppression in GBM cells may be via the reduction of ERK and Akt/mTOR signaling activities. Finally, the in vivo experiment also demonstrated that knockdown LEF1-AS1 inhibited the growth-promoting effect of LEF1-AS1 of U87 cells. CONCLUSION:Our result indicated that lncRNA LEF1-AS1 acts as an oncogene in GBM and may be a pivotal target for this disease.

Dataset Information

HIF2-Induced Long Noncoding RNA RAB11B-AS1 Promotes Hypoxia-Mediated Angiogenesis and Breast Cancer Metastasis.

Publications

HIF2-Induced Long Noncoding RNA RAB11B-AS1 Promotes Hypoxia-Mediated Angiogenesis and Breast Cancer Metastasis.

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