title: Ski prevents TGF-β-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer.
abstract: Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis, which confers cancer cells with increased motility and invasiveness, and EMT is characterized by loss of epithelial marker E-cadherin and gain of mesenchymal marker N-cadherin. Transforming growth factor-β (TGF-β) signaling is a crucial inducer of EMT in various types of cancer. Ski is an important negative regulator of TGF-β signaling, which interacts with SMADs to repress TGF-β signaling activity. Although there is accumulating evidence that Ski functions as a promoter or suppressor in human types of cancer, the molecular mechanisms by which Ski affects TGF-β-induced EMT and invasion in non-small cell lung cancer (NSCLC) are not largely elucidated. In the present study, we investigated the mechanistic role of Ski in NSCLC metastasis. Ski was significantly reduced in metastatic NSCLC cells or tissues when compared with non-metastatic NSCLC cells or tissues. Moreover, following TGF-β stimulation Ski-silenced A549 cells had more significant features of EMT and a higher invasive activity when compared with A549 cells overexpressing Ski. Mechanistically, Ski-silenced and overexpressed A549 cells showed an increase and a reduction in the SMAD3 phosphorylation level, respectively. This was supported by plasminogen activator inhibitor-1 (PAI-1) promoter activity obtained in Ski-silenced and overexpressed A549 cells. However, after treatment of SIS3 (inhibitor of SMAD3 phosphorylation) followed by TGF-β1 stimulation, we did not observe any effect of Ski on TGF-β-induced EMT, and invasion in Ski-silenced and overexpressed A549 cells. In conclusion, our findings suggest that Ski represses TGF-β-induced EMT and invasion by inhibiting SMAD-dependent signaling in NSCLC.
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Yang
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Tianjie
authors.initials: T
authors.lastname: Yang
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Longqiang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.affiliation: Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Soochow University, Medical College of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Li
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Zhang
mesh_terms: D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000096:biosynthesis / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497790:SMAD3 protein, human; D051785:Smad Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C060614:SKI protein, human