TY  - JOUR
AU  - Krebs, Markus
AU  - Kotlyar, Mischa J
AU  - Fahl, Julian
AU  - Janaki Raman, Sudha
AU  - Röhrig, Florian
AU  - Marquardt, André
AU  - Kübler, Hubert
AU  - Kneitz, Burkhard
AU  - Schulze, Almut
AU  - Kalogirou, Charis
TI  - Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with Tyrosine Kinase Inhibitors.
JO  - Urologia internationalis
VL  - 108
IS  - 1
SN  - 0042-1138
CY  - Basel
PB  - Karger
M1  - DKFZ-2024-00285
SP  - 49 - 59
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Carcinoma, Renal Cell: drug therapy
KW  - Carcinoma, Renal Cell: genetics
KW  - Carcinoma, Renal Cell: pathology
KW  - Kidney Neoplasms: drug therapy
KW  - Kidney Neoplasms: genetics
KW  - Kidney Neoplasms: pathology
KW  - Tyrosine Kinase Inhibitors
KW  - Metformin: pharmacology
KW  - Cell Line, Tumor
KW  - MicroRNAs: genetics
KW  - Sunitinib: pharmacology
KW  - Gene Expression Regulation, Neoplastic
KW  - Cell Proliferation: genetics
KW  - Vascular Endothelial Growth Factor A: metabolism
KW  - Angiogenesis (Other)
KW  - Kidney cancer (Other)
KW  - Metformin (Other)
KW  - MicroRNA (Other)
KW  - Tyrosine kinase inhibitor (Other)
KW  - Tyrosine Kinase Inhibitors (NLM Chemicals)
KW  - Metformin (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - Sunitinib (NLM Chemicals)
KW  - VEGFA protein, human (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor A (NLM Chemicals)
KW  - MIRN205 microRNA, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38035560
C2  - pmc:PMC10836959
DO  - DOI:10.1159/000535025
UR  - https://inrepo02.dkfz.de/record/287641
ER  -