MicroRNAs Targeting HIF-2α, VEGFR1 and/or VEGFR2 as Potential Predictive Biomarkers for VEGFR Tyrosine Kinase and HIF-2α Inhibitors in Metastatic Clear-Cell Renal Cell Carcinoma.
MicroRNAs Targeting HIF-2α, VEGFR1 and/or VEGFR2 as Potential Predictive Biomarkers for VEGFR Tyrosine Kinase and HIF-2α Inhibitors in Metastatic Clear-Cell Renal Cell Carcinoma.
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DOI：
10.3390/cancers13123099
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发表时间：
2021-06-21
期刊：
影响因子：
5.2
通讯作者：
Beuselinck B
中科院分区：
文献类型：
--
作者：
Kinget L;Roussel E;Verbiest A;Albersen M;Rodríguez-Antona C;Graña-Castro O;Inglada-Pérez L;Zucman-Rossi J;Couchy G;Job S;de Reyniès A;Laenen A;Baldewijns M;Beuselinck B
转移性肾透明细胞癌的特征是通过HIF-2α和VEGFR 2表达增加而增强的血管生成。VEGFR酪氨酸激酶抑制剂是转移性透明细胞肾细胞癌治疗的基石，目前正在研究针对HIF-2α的新治疗方法。然而，缺乏临床上有用的生物标志物，可以预测这些治疗的反应。MicroRNA是干扰基因翻译的小RNA分子。在这项研究中，我们确定了四种可能干扰VEGFR 1和/或VEGFR 2翻译的microRNA，并与VEGFR-TKI治疗后的肿瘤缩小和无进展生存相关。这些microRNA可能预测对VEGFR-TKI的反应。此外，我们鉴定了三种与HIF-2α表达相关的microRNA，以及VEGFR-TKI治疗后与肿瘤缩小和无进展生存相关的microRNA。这三种microRNA可能不仅能够预测VEGFR-TKI治疗的反应，还可能预测即将到来的HIF-2α抑制剂belzutifan治疗的反应。转移性透明细胞肾细胞癌（m-ccRCC）的特征是通过von Hippel-Lindau蛋白功能丧失导致缺氧诱导因子（HIF）-2α和血管内皮生长因子受体（VEGFR）依赖性血管生成增加。VEGFR酪氨酸激酶抑制剂（VEGFR-TKI）是m-ccRCC治疗的基石，目前正在研究针对HIF-2α的新治疗方法。然而，缺乏这些治疗的预测性生物标志物。在这项回顾性队列研究中，包括109例接受VEGF靶向治疗作为一线治疗的患者，我们旨在研究靶向HIF-2α、VEGFR 1和VEGFR 2的microRNA（miRNAs）的可能预测功能。我们选择了与HIF-2α、VEGFR 1和/或VEGFR 2表达负相关的miRNA，以及与相应基因中预测的靶位点负相关的miRNA，随后研究了它们对治疗结果的影响。我们鉴定了四种与VEGFR 1和/或VEGFR 2表达呈负相关的miRNA（miR-34 c-5 p、miR-221- 3 p、miR-222- 3 p和miR-3529- 3 p），并与VEGFR-TKI治疗后的肿瘤缩小和无进展生存期（PFS）相关，突出了这些miRNA的潜在预测价值。此外，我们鉴定了三种与HIF-2α表达呈负相关的miRNA（miR-185- 5 p、miR-223- 3 p和miR-3529- 3 p），并与VEGFR-TKI治疗后的肿瘤缩小和PFS相关。这三种miRNA不仅对VEGFR-TKI治疗有预测价值，而且可能对即将到来的HIF-2α抑制剂belzutifan治疗也有预测价值。
Metastatic clear-cell renal cell carcinoma is characterized by heightened angiogenesis through increased expression of HIF-2α and VEGFR2. VEGFR tyrosine kinase inhibitors are a cornerstone of metastatic clear-cell renal cell carcinoma treatment, and new treatments targeting HIF-2α are currently under investigation. However, clinically useful biomarkers that can predict response to these treatments are lacking. MicroRNAs are small RNA molecules that interfere with gene translation. In this study, we identified four microRNAs that potentially interfere with the translation of VEGFR1 and/or VEGFR2 and are associated with tumor shrinkage and progression-free survival upon treatment with VEGFR-TKIs. These microRNAs might be predictive of response to VEGFR-TKIs. Moreover, we identified three microRNAs associated with HIF-2α expression and with tumor shrinkage and progression-free survival upon treatment with VEGFR-TKIs. These three microRNAs might be able to predict response not only to treatment with VEGFR-TKIs but possibly also to treatment with the upcoming HIF-2α inhibitor belzutifan. Metastatic clear-cell renal cell carcinoma (m-ccRCC) is characterized by increased hypoxia-induced factor (HIF)-2α and vascular endothelial growth factor receptor (VEGFR)-dependent angiogenesis through loss of function of the von Hippel–Lindau protein. VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) are a cornerstone of m-ccRCC treatment, and new treatments targeting HIF-2α are currently under investigation. However, predictive biomarkers for these treatments are lacking. In this retrospective cohort study including 109 patients treated with VEGFR-targeted therapies as first-line treatment, we aimed to study the possible predictive function of microRNAs (miRNAs) targeting HIF-2α, VEGFR1 and VEGFR2. We selected miRNAs inversely correlated with HIF-2α, VEGFR1 and/or VEGFR2 expression and with predicted target sites in the respective genes and subsequently studied their impact on therapeutic outcomes. We identified four miRNAs (miR-34c-5p, miR-221-3p, miR-222-3p and miR-3529-3p) inversely correlated with VEGFR1 and/or VEGFR2 expression and associated with tumor shrinkage and progression-free survival (PFS) upon treatment with VEGFR-TKIs, highlighting the potential predictive value of these miRNAs. Moreover, we identified three miRNAs (miR-185-5p, miR-223-3p and miR-3529-3p) inversely correlated with HIF-2α expression and associated with tumor shrinkage and PFS upon treatment with VEGFR-TKIs. These three miRNAs can have a predictive value not only upon treatment with VEGFR-TKIs but possibly also upon treatment with the upcoming HIF-2α inhibitor belzutifan.
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影响因子：
14.9
作者：
Karagkouni D;Paraskevopoulou MD;Chatzopoulos S;Vlachos IS;Tastsoglou S;Kanellos I;Papadimitriou D;Kavakiotis I;Maniou S;Skoufos G;Vergoulis T;Dalamagas T;Hatzigeorgiou AG
通讯作者：
Hatzigeorgiou AG
影响因子：
3.9
作者：
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通讯作者：
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影响因子：
8
作者：
Garcia-Donas, Jesus;Beuselinck, Benoit;Rodriguez-Antona, Cristina
通讯作者：
Rodriguez-Antona, Cristina
影响因子：
4.8
作者：
Ho, J. J. David;Metcalf, Julie L.;Marsden, Philip A.
通讯作者：
Marsden, Philip A.
影响因子：
--
作者：
Dias F;Teixeira AL;Ferreira M;Adem B;Bastos N;Vieira J;Fernandes M;Sequeira MI;Maurício J;Lobo F;Morais A;Oliveira J;Kok K;Medeiros R
通讯作者：
Medeiros R