%0 Journal Article
%A Krebs, Markus
%A Kotlyar, Mischa J
%A Fahl, Julian
%A Janaki Raman, Sudha
%A Röhrig, Florian
%A Marquardt, André
%A Kübler, Hubert
%A Kneitz, Burkhard
%A Schulze, Almut
%A Kalogirou, Charis
%T Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with Tyrosine Kinase Inhibitors.
%J Urologia internationalis
%V 108
%N 1
%@ 0042-1138
%C Basel
%I Karger
%M DKFZ-2024-00285
%P 49 - 59
%D 2024
%X 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.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.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.Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors.
%K Humans
%K Carcinoma, Renal Cell: drug therapy
%K Carcinoma, Renal Cell: genetics
%K Carcinoma, Renal Cell: pathology
%K Kidney Neoplasms: drug therapy
%K Kidney Neoplasms: genetics
%K Kidney Neoplasms: pathology
%K Tyrosine Kinase Inhibitors
%K Metformin: pharmacology
%K Cell Line, Tumor
%K MicroRNAs: genetics
%K Sunitinib: pharmacology
%K Gene Expression Regulation, Neoplastic
%K Cell Proliferation: genetics
%K Vascular Endothelial Growth Factor A: metabolism
%K Angiogenesis (Other)
%K Kidney cancer (Other)
%K Metformin (Other)
%K MicroRNA (Other)
%K Tyrosine kinase inhibitor (Other)
%K Tyrosine Kinase Inhibitors (NLM Chemicals)
%K Metformin (NLM Chemicals)
%K MicroRNAs (NLM Chemicals)
%K Sunitinib (NLM Chemicals)
%K VEGFA protein, human (NLM Chemicals)
%K Vascular Endothelial Growth Factor A (NLM Chemicals)
%K MIRN205 microRNA, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38035560
%2 pmc:PMC10836959
%R 10.1159/000535025
%U https://inrepo02.dkfz.de/record/287641