TY  - JOUR
A1  - Krebs, Markus
A1  - Solimando, Antonio Giovanni
A1  - Kalogirou, Charis
A1  - Marquardt, André
A1  - Frank, Torsten
A1  - Sokolakis, Ioannis
A1  - Hatzichristodoulou, Georgios
A1  - Kneitz, Susanne
A1  - Bargou, Ralf
A1  - Kübler, Hubert
A1  - Schilling, Bastian
A1  - Spahn, Martin
A1  - Kneitz, Burkhard
T1  - miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro
T2  - Journal of Clinical Medicine
N2  - 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.
KW  - microRNA-221
KW  - high-risk Prostate Cancer
KW  - angiogenesis
KW  - Sunitinib
KW  - Tyrosine kinase inhibition
Y1  - 2020
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/20316
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-203168
SN  - 2077-0383
VL  - 9
IS  - 3
ER  -