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Cancer Lett. 2014 Nov 1;354(1):33-42. doi: 10.1016/j.canlet.2014.06.023. Epub 2014 Aug 19.

N-myc downstream-regulated gene 2 (NDRG2) suppresses the epithelial-mesenchymal transition (EMT) in breast cancer cells via STAT3/Snail signaling.

Author information

1
Department of Biological Science and the Research Center for Women's Diseases, Sookmyung Women's University, Hyochangwongil 52, Yongsan-Gu, Seoul 140-742, Republic of Korea.
2
Department of Biological Science and the Research Center for Women's Diseases, Sookmyung Women's University, Hyochangwongil 52, Yongsan-Gu, Seoul 140-742, Republic of Korea. Electronic address: jslim@sookmyung.ac.kr.

Abstract

Although NDRG2 has recently been found to be a candidate tumor suppressor, its precise role in the epithelial-mesenchymal transition (EMT) is not well understood. In the present study, we demonstrated that NDRG2 overexpression in MDA-MB-231 cells down-regulated the expression of Snail, a transcriptional repressor of E-cadherin and a key regulator of EMT, as well as the phosphorylation of signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor that is activated in many human malignancies including breast cancer. In addition, we confirmed that the expression of Snail and phospho-STAT3 was recovered when NDRG2 was knocked down by siRNA in MCF7 cells in which NDRG2 is endogenously expressed. Interestingly, MDA-MB-231-NDRG2 cells showed remarkably decreased Snail expression after treatment with JSI-124 (also known as cucurbitacin I) or Stattic, STAT3 inhibitors, compared to MDA-MB-231-mock cells. Moreover, STAT3 activation by EGF treatment induced higher Snail expression, and NDRG2 overexpression resulted in the inhibition of Snail expression in MDA-MB-231 cells stimulated by EGF in the absence or presence of STAT3 inhibitor. Treatment of MDA-MB-231 cells with STAT3 inhibitor led to a moderate decrease in wound healing and migration capacity, whereas STAT3 inhibitor treatment of MDA-MB-231-NDRG2 cells resulted in a significant attenuation of migration in both resting and EGF-stimulated cells. Collectively, our data demonstrate that the inhibition of STAT3 signaling by NDRG2 suppresses EMT progression of EMT via the down-regulation of Snail expression.

KEYWORDS:

Breast cancer; EMT; NDRG2; STAT3; Snail

PMID:
25153349
DOI:
10.1016/j.canlet.2014.06.023
[Indexed for MEDLINE]
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