Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with Tyrosine Kinase Inhibitors.

IF 1.5 4区医学 Q3 UROLOGY & NEPHROLOGY

Urologia Internationalis Pub Date : 2024-01-01 Epub Date: 2023-11-30 DOI:10.1159/000535025

Markus Krebs, Mischa J Kotlyar, Julian Fahl, Sudha Janaki Raman, Florian Röhrig, André Marquardt, Hubert Kübler, Burkhard Kneitz, Almut Schulze, Charis Kalogirou

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引用次数: 0

Abstract

Introduction: Metformin (MF) intake could be associated with a favorable outcome in sunitinib (SUT)- and axitinib (AX)-treated clear cell renal cell carcinoma (ccRCC) patients. Functionally, MF induces miR-205, a microRNA serving as a tumor suppressor in several cancers.

Methods: Real-time quantitative PCR, viability assays, and Western blotting analyzed MF and SUT/AX effects in RCC4 and 786-O cells. A tetracycline-inducible overexpression model was used to study the role of miR-205 and its known target gene, VEGFA. We analyzed miR-205 and VEGFA within a public and an in-house ccRCC cohort. Human umbilical vein endothelial cell (HUVEC) sprouting assays examined miR-205 effects on angiogenesis initiation. To determine the influence of the von Hippel-Lindau tumor suppressor (VHL), we examined VHLwt reexpressing RCC4 and 786-O cells.

Results: Viability assays confirmed a sensitizing effect of MF toward SUT/AX in RCC4 and 786-O cells. Overexpression of miR-205 diminished VEGFA expression - as did treatment with MF. Tumor tissue displayed a downregulation of miR-205 and an upregulation of VEGFA. Accordingly, miR-205 caused less and shorter vessel sprouts in HUVEC assays. Finally, VHLwt-expressing RCC4 and 786-O cells displayed higher miR-205 and lower VEGFA levels.

Conclusion: Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors.

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二甲双胍调节肾细胞癌细胞中miR-205/VEGFA轴-探索与酪氨酸激酶抑制剂的临床协同作用

二甲双胍(MF)的摄入可能与舒尼替尼(SUT)和阿西替尼(AX)治疗的透明细胞肾细胞癌(ccRCC)患者的有利结果相关。在功能上，MF诱导miR-205，一种在几种癌症中作为肿瘤抑制因子的microRNA。方法:采用qRT-PCR、活力测定和Western blotting分析MF和SUT/AX对RCC4和786-O细胞的影响。采用四环素诱导过表达模型研究miR-205及其已知靶基因VEGFA的作用。我们分析了公共和内部ccRCC队列中的miR-205和VEGFA。HUVEC(人脐静脉内皮细胞)发芽试验检测了miR-205对血管生成起始的影响。为了确定von Hippel-Lindau肿瘤抑制因子(VHL)的影响，我们检测了VHL - wt重新表达RCC4和786-O细胞。结果:活性测定证实了MF对RCC4和786-O细胞SUT/AX的增敏作用。miR-205的过表达降低了VEGFA的表达-与MF治疗一样。肿瘤组织显示miR-205下调，VEGFA上调。因此，在HUVEC实验中，miR-205导致更少、更短的血管芽。最后，表达RCC4的VHLwt和786-O细胞显示更高的miR-205和更低的VEGFA水平。结论:我们的研究结果支持MF在ccRCC中的保护作用，并为与酪氨酸激酶抑制剂(TKI)的临床协同作用提供功能见解。

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来源期刊

Urologia Internationalis 医学-泌尿学与肾脏学

CiteScore

3.30

自引率

6.20%

发文量

审稿时长

3-8 weeks

期刊介绍： Concise but fully substantiated international reports of clinically oriented research into science and current management of urogenital disorders form the nucleus of original as well as basic research papers. These are supplemented by up-to-date reviews by international experts on the state-of-the-art of key topics of clinical urological practice. Essential topics receiving regular coverage include the introduction of new techniques and instrumentation as well as the evaluation of new functional tests and diagnostic methods. Special attention is given to advances in surgical techniques and clinical oncology. The regular publication of selected case reports represents the great variation in urological disease and illustrates treatment solutions in singular cases.