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

Autor:	Krebs M; Department of Urology and Pediatric Urology, University Hospital Würzburg, Würzburg, Germany.; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany., Kotlyar MJ; Department of Urology and Pediatric Urology, University Hospital Würzburg, Würzburg, Germany, mischa.kotlyar@gmail.com.; Department of Interdisciplinary Critical Care Medicine and Intermediate Care, Helios Clinic Erfurt, Erfurt, Germany, mischa.kotlyar@gmail.com., Fahl J; Department of Urology and Pediatric Urology, University Hospital Würzburg, Würzburg, Germany., Janaki Raman S; Chair of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany., Röhrig F; Chair of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany., Marquardt A; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany.; Institute of Pathology, Klinikum Stuttgart, Stuttgart, Germany., Kübler H; Department of Urology and Pediatric Urology, University Hospital Würzburg, Würzburg, Germany., Kneitz B; Department of Urology and Pediatric Urology, University Hospital Würzburg, Würzburg, Germany., Schulze A; Chair of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.; Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Heidelberg, Germany., Kalogirou C; Department of Urology and Pediatric Urology, University Hospital Würzburg, Würzburg, Germany.
Jazyk:	angličtina
Zdroj:	Urologia internationalis [Urol Int] 2024; Vol. 108 (1), pp. 49-59. Date of Electronic Publication: 2023 Nov 30.
DOI:	10.1159/000535025
Abstrakt:	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. (© 2023 The Author(s). Published by S. Karger AG, Basel.)
Databáze:	MEDLINE
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