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<p>This study aimed to assess the molecular effects of the miR- 155 - 5p in modulating Temozolomide chemosensitivity, which was examined utilizing in silico and in vitro methods on brain cancer stem cells (BCSCs) that exhibit high differentiation, apoptosis avoidance, and a remarkable capacity for self-renewal as a mechanism of chemotherapeutic resistance. The hypothesis of the study is how miR- 155 - 5p modulates temozolomide chemosensitivity in brain cancer stem cells (BCSCs) and their differentiated counterparts (BSCs) and whether it influences the molecular mechanisms underlying tumour recurrence and treatment failure. By silencing miR- 155 - 5p using anti-miR oligonucleotides, the knockdown efficiency of miR- 155 - 5p was confirmed via quantitative qRT-PCR. The increased chemosensitivity effect of miR- 155 - 5p against temozolomide in BCSCs and BCSs was measured by cytotoxicity assay. Subsequently, all studied groups were evaluated by performing cell viability, cell cycle, and apoptosis tests. miRNA-mRNA-pathway interactions were analyzed using different bioinformatics tools and databases. Cell viability was significantly reduced by 42.9% in the combined treatment (anti-miR- 155 - 5p + temozolomide) group compared to the untreated group. Temozolomide treatment in combination with anti-miR- 155 - 5p showed a significant decrease in cell viability compared to temozolomide alone. In contrast, late apoptosis increased 2.10-fold (<i>p</i> &lt; 0.0001), indicating a synergistic effect in promoting late apoptosis. Combining temozolomide and anti-miR- 155 - 5p inhibits DNA synthesis by causing G2 phase arrest. mRNAs targeted by miR- 155 - 5p and significantly down-regulated in glioblastoma included <i>GABRA1</i>, <i>GABRB2</i>, <i>SCN1A</i>, <i>GRIN2A</i>, and <i>SGIP1</i>. By survival analysis, low expression of <i>SCN1A</i> was associated with poor prognosis (<i>p</i> &lt; 0.05; HR = 0.7), highlighting its potential prognostic role. The combination of temozolomide treatment with suppression of miR- 155 - 5p may provide a more effective and side-effect minimized brain cancer treatment strategy by reducing resistance.</p>

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Anti-miRNA- 155 - 5p enhances the cytotoxic efficacy of temozolomide in brain cancer stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月11日

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  • Lütfiye Ozpak,
  • Bakiye Göker Bağca,
  • Çiğir Biray Avci,
  • Cumhur Gündüz,
  • Burak Durmaz

摘要

This study aimed to assess the molecular effects of the miR- 155 - 5p in modulating Temozolomide chemosensitivity, which was examined utilizing in silico and in vitro methods on brain cancer stem cells (BCSCs) that exhibit high differentiation, apoptosis avoidance, and a remarkable capacity for self-renewal as a mechanism of chemotherapeutic resistance. The hypothesis of the study is how miR- 155 - 5p modulates temozolomide chemosensitivity in brain cancer stem cells (BCSCs) and their differentiated counterparts (BSCs) and whether it influences the molecular mechanisms underlying tumour recurrence and treatment failure. By silencing miR- 155 - 5p using anti-miR oligonucleotides, the knockdown efficiency of miR- 155 - 5p was confirmed via quantitative qRT-PCR. The increased chemosensitivity effect of miR- 155 - 5p against temozolomide in BCSCs and BCSs was measured by cytotoxicity assay. Subsequently, all studied groups were evaluated by performing cell viability, cell cycle, and apoptosis tests. miRNA-mRNA-pathway interactions were analyzed using different bioinformatics tools and databases. Cell viability was significantly reduced by 42.9% in the combined treatment (anti-miR- 155 - 5p + temozolomide) group compared to the untreated group. Temozolomide treatment in combination with anti-miR- 155 - 5p showed a significant decrease in cell viability compared to temozolomide alone. In contrast, late apoptosis increased 2.10-fold (p < 0.0001), indicating a synergistic effect in promoting late apoptosis. Combining temozolomide and anti-miR- 155 - 5p inhibits DNA synthesis by causing G2 phase arrest. mRNAs targeted by miR- 155 - 5p and significantly down-regulated in glioblastoma included GABRA1, GABRB2, SCN1A, GRIN2A, and SGIP1. By survival analysis, low expression of SCN1A was associated with poor prognosis (p < 0.05; HR = 0.7), highlighting its potential prognostic role. The combination of temozolomide treatment with suppression of miR- 155 - 5p may provide a more effective and side-effect minimized brain cancer treatment strategy by reducing resistance.