title: Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype.
abstract: In a breast tumor xenograft model, the MCT-1 oncogene increases the in vivo tumorgenicity of MCF7 cells by promoting angiogenesis and inhibiting apoptosis. Increases in the tumor microvascular density are accompanied by a strong reduction in the levels of the angiogenesis inhibitor thrombospondin-1 (TSP1), but the mechanisms underlying this process are unknown. We show that TSP1 expression is controlled, at least in part, by post-transcriptional events. Using RNA interference to knock down the expression of the RNA-binding protein HuR in MCF7 cells as well as HuR overexpression, we demonstrate that HuR plays an important role in translation of the TSP1 mRNA. Furthermore, employing the RIP-Chip assay yielded 595 transcripts with significantly altered binding to HuR in the more tumorigenic breast cancer clones compared with the weakly tumorigenic clones. These mRNAs clustered in several pathways implicated in the transformed phenotype, such as the RAS pathway (involved in mitogenesis), the PI3K pathway (evasion of apoptosis) and pathways mediating angiogenesis and the cellular response to hypoxia. These findings demonstrate for the first time that global changes in HuR-bound mRNAs are implicated in the evolution to a more tumorigenic phenotype in an in vivo tumor model and underscore the role of global mRNA-protein interactions toward tumor progression.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mazan-Mamczarz
authors.forename: P R
authors.initials: PR
authors.lastname: Hagner
authors.forename: S
authors.initials: S
authors.lastname: Corl
authors.forename: S
authors.initials: S
authors.lastname: Srikantan
authors.forename: W H
authors.initials: WH
authors.lastname: Wood
authors.forename: K G
authors.initials: KG
authors.lastname: Becker
authors.forename: M
authors.initials: M
authors.lastname: Gorospe
authors.forename: J D
authors.initials: JD
authors.lastname: Keene
authors.forename: A S
authors.initials: AS
authors.lastname: Levenson
authors.forename: R B
authors.initials: RB
authors.lastname: Gartenhaus
mesh_terms: D000954:Antigens, Surface / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015513:Oncogene Proteins / Q000502:physiology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D000954:Antigens, Surface; D018797:Cell Cycle Proteins; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C115081:MCTS1 protein, human; D015513:Oncogene Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D019700:Thrombospondin 1; D019869:Phosphatidylinositol 3-Kinases