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Exp Cell Res. 2013 Mar 10;319(5):740-9. doi: 10.1016/j.yexcr.2012.10.013. Epub 2012 Nov 5.

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

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  • 1Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin 300052, China.

Abstract

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID:
23137649
[PubMed - indexed for MEDLINE]
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