Oncotarget

Research Papers:

Secreted uPAR isoform 2 (uPAR7b) is a novel direct target of miR-221

Natalie Falkenberg _, Nataša Anastasov, Annalisa Schaub, Vanja Radulovic, Manfred Schmitt, Viktor Magdolen and Michaela Aubele

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Oncotarget. 2015; 6:8103-8114. https://doi.org/10.18632/oncotarget.3516

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Abstract

Natalie Falkenberg1, Nataša Anastasov2, Annalisa Schaub1, Vanja Radulovic2, Manfred Schmitt3, Viktor Magdolen3 and Michaela Aubele1

1 Institute of Pathology, German Research Center for Environmental Health, Neuherberg, Germany

2 Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

3 Clinical Research Unit, Department of Obstetrics and Gynecology, Technische Universität München, München, Germany

Correspondence to:

Natalie Falkenberg, email:

Keywords: therapy, microRNA, miR-222, PLAUR, soluble

Received: November 20, 2014 Accepted: February 03, 2015 Published: March 10, 2015

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.


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