title: N-myc downstream-regulated gene 2 (NDRG2) suppresses the epithelial-mesenchymal transition (EMT) in breast cancer cells via STAT3/Snail signaling.
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.
authors.affiliation: 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.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Lim
authors.affiliation: 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.
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Myeong-Sok
authors.initials: MS
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Lim
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014945:Wound Healing
chemical_list: C466228:NDRG2 protein, human; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
keywords: Breast cancer; EMT; NDRG2; STAT3; Snail