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<p>High-grade gliomas (HGGs) are the most aggressive adult brain tumors, with a dismal median survival of approximately 15&#xa0;months, highlighting the need for novel therapeutic strategies. In a prior immunotherapy trial using dendritic cells against glioblastoma, miR-216b emerged as a potential predictive biomarker. Thus, we hypothesize that miR-216b impacts glioma aggressiveness and thereby therapeutic success. Here, we demonstrate that miR-216b is significantly downregulated in the majority of Isocitrate dehydrogenase 1/2 (IDH) wild-type HGG tissue samples (n = 42) and cell models (n = 18). Functional assays revealed that miR-216b overexpression impairs glioma cell proliferation, migration, and stemness characteristics. Transcriptomic and target prediction analyses identified <i>CDK4</i>, a key cell cycle regulator, as a direct target of miR-216b, confirmed via luciferase reporter assays. Correspondingly, upregulating miR-216b (mimic) via transfection decreased CDK4 mRNA and protein levels accompanied by a p21-dependent increase of cells in G0/G1 phase. In addition, miR-216b expression correlated with increased sensitivity to the CDK4/6 inhibitor Abemaciclib. Notably, miR-216b levels were significantly higher in less aggressive IDH-mutant gliomas (n = 21), linking its downregulation to malignancy grade. Collectively, our findings discovered miR-216b as a tumor suppressor in HGGs, modulating CDK4 expression and affecting the responsiveness to CDK4/6 inhibitors. The observed results support the potential of miR-216b as both a prognostic and predictive indicator in HGGs.</p>

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Tumor-suppressive role of miR-216b impacts cell cycle regulation in high-grade glioma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月6日

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  • Alexandra Lang,
  • Sabine Buerger,
  • Leah Mager,
  • Lea Erjavc,
  • Barbara Kiesel,
  • Sibylle Madlener,
  • Carola Nadine Jaunecker,
  • Linda Pacher,
  • Finn Christopher Robert,
  • Leonie Krausgruber,
  • Andrezza Nascimento,
  • Sarah Machreich,
  • Gerda Ricken,
  • Lisa Gabler-Pamer,
  • Anna Laemmerer,
  • Sabine Spiegl-Kreinecker,
  • Matthias Hackl,
  • Marianne Pultar,
  • Johannes Reisecker,
  • Katharina Bruckner,
  • Barbara Neudert,
  • Leonhard Muellauer,
  • Dominik Kirchhofer,
  • Mario Mischkulnig,
  • Anna Sophie Berghoff,
  • Adelheid Woehrer,
  • Daniel Senfter,
  • Karl Roessler,
  • Thomas Roetzer-Pejrimovsky,
  • Walter Berger,
  • Johannes Andreas Hainfellner,
  • Romana Hoeftberger,
  • Georg Widhalm,
  • Friedrich Erhart,
  • Daniela Lötsch-Gojo

摘要

High-grade gliomas (HGGs) are the most aggressive adult brain tumors, with a dismal median survival of approximately 15 months, highlighting the need for novel therapeutic strategies. In a prior immunotherapy trial using dendritic cells against glioblastoma, miR-216b emerged as a potential predictive biomarker. Thus, we hypothesize that miR-216b impacts glioma aggressiveness and thereby therapeutic success. Here, we demonstrate that miR-216b is significantly downregulated in the majority of Isocitrate dehydrogenase 1/2 (IDH) wild-type HGG tissue samples (n = 42) and cell models (n = 18). Functional assays revealed that miR-216b overexpression impairs glioma cell proliferation, migration, and stemness characteristics. Transcriptomic and target prediction analyses identified CDK4, a key cell cycle regulator, as a direct target of miR-216b, confirmed via luciferase reporter assays. Correspondingly, upregulating miR-216b (mimic) via transfection decreased CDK4 mRNA and protein levels accompanied by a p21-dependent increase of cells in G0/G1 phase. In addition, miR-216b expression correlated with increased sensitivity to the CDK4/6 inhibitor Abemaciclib. Notably, miR-216b levels were significantly higher in less aggressive IDH-mutant gliomas (n = 21), linking its downregulation to malignancy grade. Collectively, our findings discovered miR-216b as a tumor suppressor in HGGs, modulating CDK4 expression and affecting the responsiveness to CDK4/6 inhibitors. The observed results support the potential of miR-216b as both a prognostic and predictive indicator in HGGs.