MiR-7, Inhibited Indirectly by LincRNA HOTAIR, Directly Inhibits SETDB1 and Reverses the EMT of Breast Cancer Stem Cells by Downregulating the STAT3 Pathway

Authors

  • Hongyi Zhang,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
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  • Kai Cai,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
    2. Department of Tumor-Bio Therapy, Cancer center of People's Liberation Army, Hospital of People's Liberation Army, Nanjing, China
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  • Jing Wang,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
    2. Department of Gynecology and Obstetrics, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
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  • Xiaoying Wang,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
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  • Kai Cheng,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
    2. Department of Pathology, Nanjing Jinling Hospital, Nanjing University Medicine School, Nanjing, China
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  • Fangfang Shi,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
    2. Department of Oncology, Zhongda Hospital, Southeast University, Nanjing, China
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  • Longwei Jiang,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
    2. Department of Tumor-Bio Therapy, Cancer center of People's Liberation Army, Hospital of People's Liberation Army, Nanjing, China
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  • Yunxia Zhang,

    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
    2. Department of Gynecology and Obstetrics, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
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  • Jun Dou

    Corresponding author
    1. Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China
    • Correspondence: Jun Dou, M.D. Ph.D., Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing 210009, China. Telephone: +86-25-83272454; Fax: +86-25-83272295; e-mail: njdoujun@seu.edu.cn

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Abstract

Epithelial–mesenchymal transition (EMT) contributes to tumor invasion and metastasis in many cancers and correlates highly with the acquisition of cancer stem cell (CSC) characteristics. EMT also correlates with changes in specific microRNAs (miRNAs) that have already been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. Here, we show that miR-7, which was downregulated in breast CSCs (BCSCs) isolated from the human MCF-7 and MDA-MB-231 cell lines, inhibited cell invasion and metastasis, decreased the BCSC population and partially reversed EMT in MDA-MB-231 cells by directly targeting the oncogene, SETDB1. The conspicuous epigenetic transition induced by miR-7 overexpression was found not only in MDA-MB-231 cells but also in BCSC xenograft tumors. MiR-7 inhibited the metastasis of BCSCs in lungs, kidneys, and adrenal glands of NOD/SCID mice. ChIP-polymerase chain reaction result suggested that the SETDB1 induced STAT3 expression by binding to the promoter of STAT3. MiR-7-mediated downregulation of SETDB1 resulted in the suppression of STAT3, which led to the downregulation of c-myc, twist, and mir-9. In addition, the downregulation of miR-7 in BCSCs may be indirectly attributed to lincRNA HOTAIR by modulating the expression of HoxD10 that promotes the expression of miR-7. These findings demonstrate that miR-7 was a tumor suppressor and that the overexpression of miR-7 might serve as a good strategy for treating highly invasive breast cancer. Stem Cells 2014;32:2858–2868

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