title: Characterization of dual PTEN and p53-targeting microRNAs identifies microRNA-638/Dnm2 as a two-hit oncogenic locus.
abstract: Tumor suppressor genes (TSGs) are often concomitantly lost or mutated in human cancers and have been shown to act synergistically to promote tumorigenesis. In addition to genomic alterations, posttranscriptional regulation by microRNAs (miRNAs) represents another mechanism by which TSG expression is dysregulated in cancers. Although miRNAs that target critical TSGs such as PTEN or p53 have been identified, little is known about miRNAs that concomitantly regulate both these key TSGs. In this study, we characterize microRNA 518c(∗) (miR-518c(∗)) and miR-638 as dual PTEN- and p53-targeting miRNAs that are upregulated in multiple human cancers. We focus on miR-638 and show that it associates independently with these two tumor suppressor transcripts as well as BRCA1, a known miR-638 target. We find that miR-638 overexpression promotes tumorigenesis and demonstrate cooperativity between miR-638 and its host gene Dnm2, suggesting that the Dnm2 locus encodes two distinct oncogenic components that play important roles in tumorigenesis.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Tay
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shen Mynn
authors.initials: SM
authors.lastname: Tan
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Florian A
authors.initials: FA
authors.lastname: Karreth
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: ppandolf@bidmc.harvard.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism*; D034285:Dynamin II / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019313:BRCA1 Protein; C571457:MIRN518 microRNA, human; C572154:MIRN638 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; D034285:Dynamin II
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