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Updated: Jul 9, 2025

Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
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Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with

Markus Krebs1,2, Mischa J Kotlyar3,4, Julian Fahl1

  • 1Department of Urology and Pediatric Urology, University Hospital Würzburg, Würzburg, Germany.

Urologia Internationalis
|November 30, 2023
PubMed
Abstract

Insights

Metformin enhances sunitinib and axitinib effectiveness in clear cell renal cell carcinoma (ccRCC) by increasing miR-205, a tumor suppressor microRNA. This mechanism reduces VEGFA and inhibits angiogenesis, supporting metformin's protective role in ccRCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Metformin (MF) intake may improve outcomes for clear cell renal cell carcinoma (ccRCC) patients treated with sunitinib (SUT) or axitinib (AX).
  • Metformin induces miR-205, a microRNA with known tumor-suppressive functions in various cancers.

Purpose of the Study:

  • To investigate the functional role of metformin in ccRCC treatment, specifically its effect on miR-205 and VEGFA.
  • To explore the synergistic effects of metformin with tyrosine kinase inhibitors (SUT/AX) in ccRCC.

Main Methods:

  • Real-time quantitative PCR, viability assays, and Western blotting were used to analyze metformin and SUT/AX effects in ccRCC cell lines.
  • A tetracycline-inducible model was employed to study miR-205 and its target VEGFA, alongside analyses of ccRCC patient cohorts.
  • HUVEC sprouting assays and VHLwt reexpression experiments assessed the impact of miR-205 on angiogenesis and VHL status.

Main Results:

  • Metformin sensitized ccRCC cells to SUT/AX, and miR-205 overexpression or metformin treatment reduced VEGFA levels.
  • Tumor tissues showed decreased miR-205 and increased VEGFA expression, correlating with reduced angiogenesis in vitro.
  • Restoration of VHL (VHLwt) in ccRCC cells led to higher miR-205 and lower VEGFA levels.

Conclusions:

  • Metformin plays a protective role in ccRCC, potentially through miR-205 induction.
  • The findings provide functional insights into the clinical synergy observed between metformin and tyrosine kinase inhibitors in ccRCC treatment.
Keywords:
AngiogenesisKidney cancerMetforminMicroRNATyrosine kinase inhibitor

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