title: nm23-H1 is a negative regulator of TGF-β1-dependent induction of epithelial-mesenchymal transition.
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.
authors.affiliation: Tianjin 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.
authors.forename: Rongzhi
authors.initials: R
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.forename: Daxing
authors.initials: D
authors.lastname: Zhu
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D008156:Luciferases; C517938:NME1 protein, human