title: Secreted uPAR isoform 2 (uPAR7b) is a novel direct target of miR-221.
abstract: miR-221/-222 and components of the urokinase-type plasminogen activator system (uPAS) are associated with metastasis and poor prognosis in breast cancer, including the triple-negative subtype (TNBC). Modification of components of uPAS and involved miRNAs may contribute to targeted therapy for breast cancer patients. miR-221-/-222-overexpressing or miR-221-depleted cells were employed for qRT-PCR and Western blots to show associations of uPAR with miR-221/-222. To substantiate direct targeting of miR-221/-222 within 3' UTR of the uPAR isoform 2, in silico analysesand in vitro assays were conducted. Significant associations between miR-221 and uPAR isoform 2 expressions were observed at the mRNA and protein levels in breast cancer cells representing TNBC. For the first time, the uPAR isoform 2 was demonstrated as direct target for miR-221/-222. Inhibition of miR-221 reduced uPAR protein expression and expression of the tumor cell invasion markers vimentin and RHOC. These results demonstrate a direct and positive regulation of the secreted uPAR isoform 2 by miR-221, increasing its protein expression, a prerequisite for malignancy, while the other uPAR isoforms (1, 3 and 4) are indirectly regulated through miR-10b and miR-221/-222. By targeting uPAR isoforms and/or miRNA-221/-222, the diagnosis and therapy of breast cancer, in particular in TNBC, could be significantly improved.
authors: Institute of Pathology, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Natalie
authors: N
authors: Falkenberg
authors: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Nataša
authors: N
authors: Anastasov
authors: Institute of Pathology, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Annalisa
authors: A
authors: Schaub
authors: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Vanja
authors: V
authors: Radulovic
authors: Clinical Research Unit, Department of Obstetrics and Gynecology, Technische Universität München, München, Germany.
authors: Manfred
authors: M
authors: Schmitt
authors: Clinical Research Unit, Department of Obstetrics and Gynecology, Technische Universität München, München, Germany.
authors: Viktor
authors: V
authors: Magdolen
authors: Institute of Pathology, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Michaela
authors: M
authors: Aubele
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011379:Prognosis; D020033:Protein Isoforms; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D020033:Protein Isoforms; D055293:Receptors, Urokinase Plasminogen Activator; C547183:MIRN10 microRNA, human; C525709:MIR221, human
keywords: PLAUR; miR-222; microRNA; soluble; therapy