title: Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition.
abstract: Inflammation can act as a crucial mediator of epithelial-to-mesenchymal transition (EMT). In this study, we show that oncostatin M (OSM) is expressed in an autocrine/paracrine fashion in invasive breast carcinoma. OSM stimulation promotes spontaneous lung metastasis of MCF-7 xenografts in nude mice. A conspicuous epigenetic transition was induced by OSM stimulation not only in breast cancer cell lines but also in MCF-7 xenografts in nude mice. The expression of miR-200 and let-7 family members in response to OSM stimulation was downregulated in a signal transducer and activator of transcription factor 3 (Stat3)-dependent manner, resulting in comprehensive alterations of the transcription factors and oncoproteins targeted by these microRNAs. Inhibition of Stat3 activation or the ectopic expression of let-7 and miR-200 effectively reversed the mesenchymal phenotype of breast cancer cells. Stat3 promotes the transcription of Lin-28 by directly binding to the Lin-28 promoter, resulting in the repression of let-7 expression and concomitant upregulation of the let-7 target, high-mobility group A protein 2 (HMGA2). Knock down of HMGA2 significantly impairs OSM-driven EMT. Our data indicate that downregulation of let-7 and miR-200 levels initiates and maintains OSM-induced EMT phenotypes, and HMGA2 acts as a master switch of OSM-induced EMT. These findings highlight the importance of Stat3-coordinated Lin-28B-let-7-HMGA2 and miR-200-ZEB1 circuits in the cytokine-mediated phenotypic reprogramming of breast cancer cells.
authors: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: L
authors: L
authors: Guo
authors: C
authors: C
authors: Chen
authors: M
authors: M
authors: Shi
authors: F
authors: F
authors: Wang
authors: X
authors: X
authors: Chen
authors: D
authors: D
authors: Diao
authors: M
authors: M
authors: Hu
authors: M
authors: M
authors: Yu
authors: L
authors: L
authors: Qian
authors: N
authors: N
authors: Guo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D025743:HMGA2 Protein / Q000096:biosynthesis / Q000235:genetics; D064593:Heterografts; D018398:Homeodomain Proteins; D006801:Humans; D007249:Inflammation; D051741:Kruppel-Like Transcription Factors; D008175:Lung Neoplasms / Q000556:secondary; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D009368:Neoplasm Transplantation; D053683:Oncostatin M / Q000096:biosynthesis / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D025743:HMGA2 Protein; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C488352:Lin-28 protein, mouse; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; C542687:mirnlet7 microRNA, mouse; D053683:Oncostatin M