title: Repression of TIF1γ by SOX2 promotes TGF-β-induced epithelial-mesenchymal transition in non-small-cell lung cancer.
abstract: TIF1γ is a novel regulator of transforming growth factor (TGF)-β/Smad signaling. Our previous studies show that dysregulated expression of transcriptional intermediary factor 1 γ (TIF1γ) and abnormal TGF-β/Smad signaling are implicated in non-small-cell lung cancer (NSCLC) separately. However, how TIF1γ contributes to NSCLC by controlling TGF-β/Smad signaling is poorly understood. Here, we investigated the mechanistic role of TIF1γ in TGF-β-induced epithelial-mesenchymal transition (EMT), as well as a link between TIF1γ and SOX2 in NSCLC. We show that TIF1γ is a downstream target of SOX2 in NSCLC cells. SOX2 overexpression negatively regulated TIF1γ promoter activity and thereby attenuated TIF1γ mRNA and protein expression levels; SOX2 knockdown significantly enhanced TIF1γ promoter activity and augmented TIF1γ expression. Moreover, TIF1γ mRNA expression was downregulated in human NSCLC tissues and negatively correlated with SOX2 protein, which was upregulated in NSCLC tissues. Importantly, knockdown of TIF1γ or SOX2 overexpression augmented SMAD4 (human Mad (mothers against decapentaplegic)-related homologous protein 4)-dependent transcriptional responses, and enhanced TGF-β-induced EMT and human NSCLC cell invasion; knockdown of SOX2 impaired TGF-β-induced EMT and NSCLC cell invasion. In an in vivo model of metastasis, knockdown of TIF1γ promotes NSCLC cell metastasis. In addition, our data suggested that TIF1γ inhibited TGF-β-induced EMT through competing with SMAD4 in NSCLC cells. Taken together, our findings reveal a new mechanism by which SOX2-mediated transcription repression of TIF1γ promotes TGF-β-induced EMT in NSCLC.
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.|Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.|Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.|Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.|Department of Thoracic and Cardiovascular Surgery, First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Second Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Systems Biology Laboratory, Research Programs Unit, Genome-Scale Biology, and Institute of Biomedicine, Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.affiliation: Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.|Department of Thoracic and Cardiovascular Surgery, First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.|Department of Thoracic and Cardiovascular Surgery, First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.|Department of Thoracic and Cardiovascular Surgery, First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.|Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.|Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, China.
authors.forename: H-T
authors.initials: HT
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C511956:TRIM33 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta