title: MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway.
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.
authors: Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, China.
authors: Hongyi
authors: H
authors: Zhang
authors: Kai
authors: K
authors: Cai
authors: Jing
authors: J
authors: Wang
authors: Xiaoying
authors: X
authors: Wang
authors: Kai
authors: K
authors: Cheng
authors: Fangfang
authors: F
authors: Shi
authors: Longwei
authors: L
authors: Jiang
authors: Yunxia
authors: Y
authors: Zhang
authors: Jun
authors: J
authors: Dou
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011496:Protein Methyltransferases / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D011495:Histone-Lysine N-Methyltransferase; D035683:MicroRNAs; D011496:Protein Methyltransferases; D062085:RNA, Long Noncoding; D050796:STAT3 Transcription Factor; C561566:HOTAIR long untranslated RNA, human; C549242:MIRN7-1 microRNA, human; C494086:STAT3 protein, human; C454062:SETDB1 protein, human
keywords: Breast cancer stem cells; Epithelial-mesenchymal transition; SETDB1; Signal transducers and activators of transcription 3; miR-7