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

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy

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Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany

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Interdisciplinary Center for Clinical Research, University Hospital Würzburg, 97080 Würzburg, Germany

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Department of Urology, Martha-Maria Hospital Nuremberg, 90491 Nuremberg, Germany

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Chair of Physiological Chemistry, University of Würzburg, 97074 Würzburg, Germany

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Department of Dermatology, University Hospital Würzburg, 97080 Würzburg, Germany

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Department of Urology, Lindenhofspital Bern, 3012 Bern, Switzerland

Authors to whom correspondence should be addressed.

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Markus Krebs and Antonio Giovanni Solimando contributed equally to this work and should be considered co-first authors.

J. Clin. Med. 2020, 9(3), 670; https://doi.org/10.3390/jcm9030670

Received: 11 February 2020 / Revised: 24 February 2020 / Accepted: 25 February 2020 / Published: 2 March 2020

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

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Abstract

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 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. View Full-Text

Keywords: microRNA-221; high-risk Prostate Cancer; angiogenesis; Sunitinib; Tyrosine kinase inhibition

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MDPI and ACS Style

Krebs, M.; Solimando, A.G.; Kalogirou, C.; Marquardt, A.; Frank, T.; Sokolakis, I.; Hatzichristodoulou, G.; Kneitz, S.; Bargou, R.; Kübler, H.; Schilling, B.; Spahn, M.; Kneitz, B. miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro. J. Clin. Med. 2020, 9, 670. https://doi.org/10.3390/jcm9030670

AMA Style

Krebs M, Solimando AG, Kalogirou C, Marquardt A, Frank T, Sokolakis I, Hatzichristodoulou G, Kneitz S, Bargou R, Kübler H, Schilling B, Spahn M, Kneitz B. miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro. Journal of Clinical Medicine. 2020; 9(3):670. https://doi.org/10.3390/jcm9030670

Chicago/Turabian Style

Krebs, Markus, Antonio G. Solimando, Charis Kalogirou, André Marquardt, Torsten Frank, Ioannis Sokolakis, Georgios Hatzichristodoulou, Susanne Kneitz, Ralf Bargou, Hubert Kübler, Bastian Schilling, Martin Spahn, and Burkhard Kneitz. 2020. "miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro" Journal of Clinical Medicine 9, no. 3: 670. https://doi.org/10.3390/jcm9030670

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

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