nm23-H1 is a negative regulator of TGF-β1-dependent induction of epithelial–mesenchymal transition

• Published in: Experimental cell research Vol. 319; no. 5; pp. 740 - 749
• Main Authors: Zhao, Rongzhi, Gong, Lei, Li, Lin, Guo, Lili, Zhu, Daxing, Wu, Zhihao, Zhou, Qinghua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.03.2013
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; beta Catenin - genetics; beta Catenin - metabolism; Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Cell Movement; Cell Proliferation; embryogenesis; Epithelial-Mesenchymal Transition; fibronectins; Flow Cytometry; Fluorescent Antibody Technique; Humans; Luciferases - metabolism; Lung cancer metastasis; lung neoplasms; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; metastasis; Metastasis suppressor; migratory behavior; neoplasm cells; NM23 Nucleoside Diphosphate Kinases - genetics; NM23 Nucleoside Diphosphate Kinases - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Src kinase; transcription factors; transforming growth factor beta 1; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-β; Tumor Cells, Cultured; tumor suppressor genes; Wound Healing; Lung cancer metastasis; Epithelial–mesenchymal transition; Src kinase; Metastasis suppressor; Transforming growth factor-β
• DOI: 10.1016/j.yexcr.2012.10.013
• ISSN: 0014-4827; 1090-2422

Members of transforming growth factor-β(TGF-β) family are the main inducers of epithelial–mesenchymal transition (EMT) during embryogenesis and cancer pathogenesis. However, a significant crosstalk between TGF-β and other signals occurs during the induction of EMT. nm23-H1 was the first metastasis suppressor gene to be identified on the basis of an inverse relationship between nm23-H1 expression and metastasis stage. Despite extensive studies, the mechanism underlying its ability to suppress metastasis is far from elucidated. We demonstrated here that the nm23-H1 negatively regulated TGF-β1-dependent induction of EMT in non-aggressive lung cancer cell line. nm23-H1 knockdown significantly enhanced TGF-β1-induced suppression of epithelial marker E-cadherin and upregulation of mesenchymal markers β-catenin and fibronectin. The invasive and migratory potential of lung cancer cells upon TGF-β1 treatment was also markedly enhanced by nm23-H1 knockdown. On the other hand, the effect of nm23-H1 depletion on TGF-β1-induced EMT was reversed by ectopic re-expression of shRNA-resistant nm23-H1 protein. Furthermore, TGF-β1-induced EMT potentiated by nm23-H1 depletion was partially dependent on transcriptional factor Snail expression. Finally, we found Src kinase is involved in regulation of TGF-β1-induced EMT by nm23-H1. Our results suggest a means of restoring nm23-H1 to suppress TGF-β1-induced EMT that may exploited therapeutically for the management of metastasis diseases. ► The metastasis suppressor nm23-H1 negatively regulated TGF-β1-induced EMT. ► TGF-β1-induced EMT potentiated by nm23-H1 depletion was dependent on Snail expression. ► Src kinase is involved in regulation of TGF-β1-induced EMT by nm23-H1.