title: MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA.
abstract: Transforming growth factor beta (TGF-beta) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs) in TGF-beta-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-beta-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-beta induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-beta-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3' untranslated region largely reversed the phenotype induced by miR-155 and TGF-beta. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-beta-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.
authors.affiliation: Departments of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., SRB3, Tampa, FL 33612, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kong
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Lili
authors.initials: L
authors.lastname: He
authors.forename: Jian-jun
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: William S
authors.initials: WS
authors.lastname: Dalton
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D020742:rhoA GTP-Binding Protein
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