title: A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.
abstract: Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumorsuppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.
authors: Division of Tumour Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: P Mathijs
authors: PM
authors: Voorhoeve
authors: Carlos
authors: C
authors: le Sage
authors: Mariette
authors: M
authors: Schrier
authors: Ad J M
authors: AJ
authors: Gillis
authors: Hans
authors: H
authors: Stoop
authors: Remco
authors: R
authors: Nagel
authors: Ying-Poi
authors: YP
authors: Liu
authors: Josyanne
authors: J
authors: van Duijse
authors: Jarno
authors: J
authors: Drost
authors: Alexander
authors: A
authors: Griekspoor
authors: Eitan
authors: E
authors: Zlotorynski
authors: Norikazu
authors: N
authors: Yabuta
authors: Gabriella
authors: G
authors: De Vita
authors: Hiroshi
authors: H
authors: Nojima
authors: Leendert H J
authors: LH
authors: Looijenga
authors: Reuven
authors: R
authors: Agami
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005786:Gene Expression Regulation; D005821:Genetic Techniques; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D018631:ras Proteins