MiR-208a stimulates the cocktail of SOX2 and β-catenin to inhibit the let-7 induction of self-renewal repression of breast cancer stem cells and formed miR208a/let-7 feedback loop via LIN28 and DICER1

Xin Sun, Shiwen Jiang, Jian Liu, Huangzhen Wang, Yiwen Zhang, Shou-Ching Tang, Jichang Wang, Ning Du, Chongwen Xu, Chenguang Wang, Sida Qin, Jia Zhang, Dapeng Liu, Yunfeng Zhang, Xiaojun Li, Jiansheng Wang, Jun Dong, Xin Wang, Shaohua Xu, Zhen TaoFei Xu, Jie Zhou, Tao Wang, Hong Ren

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

MiR-208a stimulates cardiomyocyte hypertrophy, fibrosis and β-MHC (β-myosin heavy chain) expression, being involved in cardiovascular diseases. Although miR-208a is known to play a role in cardiovascular diseases, its role in cancer and cancer stem cells (CSCs) remains uncertain. We identified an inverse relationship between miR-208a and let-7a in breast cancer specimens, and found that SOX2, β-catenin and LIN28 are highly expressed in patients with advanced breast cancer opposed to lesser grades. Further, we isolated ALDH1+ CSCs from ZR75-1 and MDA-MB-231 (MM-231) breast cancer cell lines to test the role of miR-208a in breast CSCs (BrCSCs). Our studies showed that overexpression of miR-208a in these cells strongly promoted the proportion of ALDH1+ BrCSCs and continuously stimulated the self-renewal ability of BrCSCs. By using siRNAs of SOX2 and/or β-catenin, we found that miR-208a increased LIN28 through stimulation of both SOX2 and β-catenin. The knockdown of either SOX2 or β-catenin only partially attenuated the functions of miR-208a. Let-7a expression was strongly inhibited in miR-208a overexpressed cancer cells, which was achieved by miR-208a induction of LIN28, and the restoration of let-7a significantly inhibited the miR-208a induction of the number of ALDH1+ cells, inhibiting the propagations of BrCSCs. In let-7a overexpressed ZR75-1 and MM-231 cells, DICER1 activity was significantly inhibited with decreased miR-208a. Let-7a failed to decrease miR-208a expression in ZR75-1 and MM-231 cells with DICER1 knockdown. Our research revealed the mechanisms through which miR-208a functioned in breast cancer and BrCSCs, and identified the miR-208a-SOX2/β-catenin- LIN28-let-7a-DICER1 regulatory feedback loop in regulations of stem cells renewal.

Original languageEnglish (US)
Pages (from-to)32944-32954
Number of pages11
JournalOncotarget
Volume6
Issue number32
DOIs
StatePublished - 2015

Keywords

  • Breast tumor
  • Cancer stem cells
  • Feedback loop
  • Let-7a
  • MiRNA-208a

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Sun, X., Jiang, S., Liu, J., Wang, H., Zhang, Y., Tang, S-C., Wang, J., Du, N., Xu, C., Wang, C., Qin, S., Zhang, J., Liu, D., Zhang, Y., Li, X., Wang, J., Dong, J., Wang, X., Xu, S., ... Ren, H. (2015). MiR-208a stimulates the cocktail of SOX2 and β-catenin to inhibit the let-7 induction of self-renewal repression of breast cancer stem cells and formed miR208a/let-7 feedback loop via LIN28 and DICER1. Oncotarget, 6(32), 32944-32954. https://doi.org/10.18632/oncotarget.5079