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 Tao & 4 others Fei Xu, Jie Zhou, Tao Wang, Hong Ren

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 - Jan 1 2015

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Catenins
Neoplastic Stem Cells
Breast Neoplasms
Breast
Cardiovascular Diseases
Myosin Heavy Chains
Cardiac Myocytes
Hypertrophy
Neoplasms
Fibrosis
Cell Count
Cell Line
Research
aldehyde dehydrogenase 1

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 6, No. 32, 01.01.2015, p. 32944-32954.

Research output: Contribution to journalArticle

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, Tao, Z, Xu, F, Zhou, J, Wang, T & 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, vol. 6, no. 32, pp. 32944-32954. https://doi.org/10.18632/oncotarget.5079
Sun, Xin ; Jiang, Shiwen ; Liu, Jian ; Wang, Huangzhen ; Zhang, Yiwen ; Tang, Shou-Ching ; Wang, Jichang ; Du, Ning ; Xu, Chongwen ; Wang, Chenguang ; Qin, Sida ; Zhang, Jia ; Liu, Dapeng ; Zhang, Yunfeng ; Li, Xiaojun ; Wang, Jiansheng ; Dong, Jun ; Wang, Xin ; Xu, Shaohua ; Tao, Zhen ; Xu, Fei ; Zhou, Jie ; Wang, Tao ; Ren, Hong. / 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. In: Oncotarget. 2015 ; Vol. 6, No. 32. pp. 32944-32954.
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AU - Sun, Xin

AU - Jiang, Shiwen

AU - Liu, Jian

AU - Wang, Huangzhen

AU - Zhang, Yiwen

AU - Tang, Shou-Ching

AU - Wang, Jichang

AU - Du, Ning

AU - Xu, Chongwen

AU - Wang, Chenguang

AU - Qin, Sida

AU - Zhang, Jia

AU - Liu, Dapeng

AU - Zhang, Yunfeng

AU - Li, Xiaojun

AU - Wang, Jiansheng

AU - Dong, Jun

AU - Wang, Xin

AU - Xu, Shaohua

AU - Tao, Zhen

AU - Xu, Fei

AU - Zhou, Jie

AU - Wang, Tao

AU - Ren, Hong

PY - 2015/1/1

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N2 - 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.

AB - 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.

KW - Breast tumor

KW - Cancer stem cells

KW - Feedback loop

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