miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro
miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro
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DOI：
10.3390/jcm9030670
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发表时间：
2020-03-01
影响因子：
3.9
通讯作者：
Kneitz, Burkhard
中科院分区：
文献类型：
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作者：
Krebs, Markus;Solimando, Antonio Giovanni;Kneitz, Burkhard
前列腺癌（PCa）中miR-221- 3 p表达下调可预测高危PCa患者的总体和癌症特异性生存期。除PCa外，miR-221- 3 p表达水平可预测肾透明细胞癌（ccRCC）患者对酪氨酸激酶抑制剂（TKI）的反应。由于miR-221- 3 p的这种作用是通过特异性靶向VEGFR 2来解释的，因此我们检查了miR-221- 3 p是否调节PCa中的VEGFR 2。首先，我们通过应用荧光素酶报告基因分析和蛋白质印迹实验证实VEGFR 2/KDR是PCa细胞中miR-221- 3 p的靶基因。尽管VEGFR 2主要在TCGA（癌症基因组图谱）数据库的PCa队列中下调，但VEGFR 2在我们的高风险PCa队列（n = 142）中上调，并预测临床进展。体外miR-221- 3 p作为PC 3细胞中TKI的逃逸机制，如增殖和凋亡测定所示。此外，我们通过分析外部微阵列数据并证明舒尼替尼暴露后miR-221- 3 p/miR-222- 3 p显著上调，证实了舒尼替尼在PC 3细胞中诱导干扰素相关基因签名。我们的研究结果为具有低miR-221- 3 p水平的高风险PCa患者提供了临床前景，因为这可以预测有利的TKI反应。除了这种治疗生态位，我们还鉴定了miR-221- 3 p的部分致癌功能作为VEGFR 2抑制的逃逸机制。
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.