title: SHOX2 is a direct miR-375 target and a novel epithelial-to-mesenchymal transition inducer in breast cancer cells.
abstract: MicroRNAs have added a new dimension to our understanding of tumorigenesis and associated processes like epithelial-to-mesenchymal transition (EMT). Here, we show that miR-375 is elevated in epithelial-like breast cancer cells, and ectopic miR-375 expression suppresses EMT in mesenchymal-like breast cancer cells. We identified short stature homeobox 2 (SHOX2) as a miR-375 target, and miR-375-mediated suppression in EMT was reversed by forced SHOX2 expression. Ectopic SHOX2 expression can induce EMT in epithelial-like breast cancer cells, whereas SHOX2 knockdown diminishes EMT traits in mesenchymal-like breast cancer cells, demonstrating SHOX2 as an EMT inducer. We show that SHOX2 acts as a transcription factor to upregulate transforming growth factor β receptor I (TβR-I) expression, and TβR-I inhibitor LY364947 abolishes EMT elicited by ectopic SHOX2 expression, suggesting that transforming growth factor β signaling is essential for SHOX2-induced EMT. Manipulating SHOX2 abundance in breast cancer cells impact in vitro invasion and in vivo dissemination. Analysis of breast tumor microarray database revealed that high SHOX2 expression significantly correlates with poor patient survival. Our study supports a critical role of SHOX2 in breast tumorigenicity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Sungguan
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Hyangsoon
authors.initials: H
authors.lastname: Noh
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Hina
authors.initials: H
authors.lastname: Rehmani
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
authors.affiliation: Department of Anatomy and Cell Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System and E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Shi-Bing
authors.initials: SB
authors.lastname: Su
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biostatistics, Georgia Regents University, Augusta, GA, USA.
authors.forename: Jaejik
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA; Research Center for Traditional Chinese Medicine Complexity System and E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: shuang@gru.edu.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D016384:Consensus Sequence; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D060787:Neoplasm Grading; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D047368:Tumor Burden
chemical_list: D018398:Homeodomain Proteins; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; C484664:SHOX2 protein, human; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
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