Krebs Markus, Solimando Antonio Giovanni, Kalogirou Charis, Marquardt André, Frank Torsten, Sokolakis Ioannis, Hatzichristodoulou Georgios, Kneitz Susanne, Bargou Ralf, Kübler Hubert, Schilling Bastian, Spahn Martin, Kneitz Burkhard
Department of Urology and Pediatric Urology, University Hospital Würzburg, 97080 Würzburg, Germany.
Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080 Würzburg, Germany.
J Clin Med. 2020 Mar 2;9(3):670. doi: 10.3390/jcm9030670.
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 ( = 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.
前列腺癌（PCa）中miR-221-3p表达下调可预测高危PCa患者的总生存期和癌症特异性生存期。除PCa外，miR-221-3p表达水平还可预测透明细胞肾细胞癌（ccRCC）患者对酪氨酸激酶抑制剂（TKI）的反应。由于miR-221-3p的这一作用是通过对VEGFR2的特异性靶向作用来解释的，我们研究了miR-221-3p在PCa中是否调节VEGFR2。首先，我们通过荧光素酶报告基因检测和蛋白质印迹实验证实VEGFR2/KDR是PCa细胞中miR-221-3p的靶基因。虽然在TCGA（癌症基因组图谱）数据库的PCa队列中VEGFR2主要下调，但在我们的高危PCa队列（n = 142）中VEGFR2上调，并预测临床进展。体外实验中，增殖和凋亡检测显示，miR-221-3p在PC3细胞中作为一种从TKI逃逸的机制发挥作用。此外，通过分析外部微阵列数据以及证明舒尼替尼暴露后miR-221-3p/miR-222-3p显著上调，我们证实舒尼替尼在PC3细胞中诱导了干扰素相关基因特征。我们的研究结果为miR-221-3p水平低的高危PCa患者提供了临床视角，因为这可以预测良好的TKI反应。除了这一治疗优势外，我们还确定了miR-221-3p作为一种从VEGFR2抑制逃逸的机制具有部分致癌功能。
