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miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-203168
  • Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays andDownregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.zeige mehrzeige weniger

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Autor(en): Markus Krebs, Antonio Giovanni Solimando, Charis Kalogirou, André Marquardt, Torsten Frank, Ioannis Sokolakis, Georgios Hatzichristodoulou, Susanne Kneitz, Ralf Bargou, Hubert Kübler, Bastian SchillingORCiD, Martin Spahn, Burkhard Kneitz
URN:urn:nbn:de:bvb:20-opus-203168
Dokumentart:Artikel / Aufsatz in einer Zeitschrift
Institute der Universität:Medizinische Fakultät / Urologische Klinik und Poliklinik
Medizinische Fakultät / Pathologisches Institut
Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Medizinische Fakultät / Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Sprache der Veröffentlichung:Englisch
Titel des übergeordneten Werkes / der Zeitschrift (Englisch):Journal of Clinical Medicine
ISSN:2077-0383
Erscheinungsjahr:2020
Band / Jahrgang:9
Heft / Ausgabe:3
Aufsatznummer:670
Originalveröffentlichung / Quelle:Journal of Clinical Medicine 2020, 9(3), 670; https://doi.org/10.3390/jcm9030670
DOI:https://doi.org/10.3390/jcm9030670
Allgemeine fachliche Zuordnung (DDC-Klassifikation):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Freie Schlagwort(e):Sunitinib; Tyrosine kinase inhibition; angiogenesis; high-risk Prostate Cancer; microRNA-221
Datum der Freischaltung:02.03.2021
Datum der Erstveröffentlichung:02.03.2020
Open-Access-Publikationsfonds / Förderzeitraum 2020
Lizenz (Deutsch):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International