Background: Due to the existence of tumor stem cells with tumorigenicity properties and resistance patterns, treatment of glioblastoma is not easy. Hypoxia is a major concern in glioblastoma therapy. Telomerase activity and telomere length alterations have been known to play a critical role in glioblastoma progression and invasion. Objective: This study aimed to investigate the effects of HSV-G47Δ oncolytic virus on telomerase and telomere length alterations in U251GBMCSCs (U251-Glioblastoma cancer stem cells) under hypoxia and normoxia conditions. Methods: U251-CSCs were exposed to the HSV-G47Δ virus in optimized MOI (Multiplicity of infection= 1/14 hours). An absolute telomere length and gene expression of telomerase subunits were determined using an absolute human telomere length quantification PCR assay. Furthermore, a bioinformatics pathway analysis was carried out to evaluate physical and genetic interactions between dysregulated genes with other potential genes and pathways. Results: Data revealed that U251CSCs had longer telomeres when exposed to HSV-G47Δ in normoxic conditions but had significantly shorter telomeres in hypoxic conditions. Furthermore, hTERC, DKC1, and TEP1 genes were significantly dysregulated in hypoxic and normoxic microenvironments. The analysis revealed that the expression of TERF2 was significantly reduced in both microenvironments, and two critical genes from the MRN complex, MER11 and RAD50, were significantly upregulated in normoxic conditions. RAD50 showed a significant downregulation pattern in the hypoxic niche. Our results suggested that repair complex in the telomeric structure could be targeted by HSV-G47Δ in both microenvironments. Conclusion: In the glioblastoma treatment strategy, telomerase and telomere complex could be potential targets for HSV-G47Δ in both microenvironments. conclusion: In glioblastoma treatment strategy, telomerase and telomere complex could be potential targets for HSV-G47∆ in both microenvironments.

中文翻译：

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HSV-G47Δ 溶瘤病毒对缺氧和常氧条件下多形性胶质母细胞瘤干细胞端粒酶和端粒长度改变的影响

背景：由于具有致瘤特性和耐药模式的肿瘤干细胞的存在，胶质母细胞瘤的治疗并不容易。缺氧是胶质母细胞瘤治疗中的一个主要问题。已知端粒酶活性和端粒长度改变在胶质母细胞瘤进展和侵袭中发挥关键作用。目的：本研究旨在探讨HSV-G47Δ溶瘤病毒在缺氧和常氧条件下对U251GBMCSC（U251-胶质母细胞瘤干细胞）端粒酶和端粒长度变化的影响。方法：U251-CSC 以优化的 MOI（感染复数 = 1/14 小时）暴露于 HSV-G47Δ 病毒。使用绝对人端粒长度定量PCR测定法测定绝对端粒长度和端粒酶亚基的基因表达。此外，还进行了生物信息学通路分析，以评估失调基因与其他潜在基因和通路之间的物理和遗传相互作用。结果：数据显示，在常氧条件下暴露于 HSV-G47Δ 时，U251CSC 具有较长的端粒，但在缺氧条件下，其端粒明显较短。此外，hTERC、DKC1 和 TEP1 基因在缺氧和常氧微环境中显着失调。分析显示，TERF2 的表达在两种微环境中均显着降低，并且来自 MRN 复合物的两个关键基因 MER11 和 RAD50 在常氧条件下显着上调。RAD50 在缺氧环境中显示出显着的下调模式。我们的结果表明，在两种微环境中，HSV-G47Δ 都可以靶向端粒结构中的修复复合物。结论：在胶质母细胞瘤治疗策略中，端粒​​酶和端粒复合物可能是两种微环境中 HSV-G47Δ 的潜在靶标。结论：在胶质母细胞瘤治疗策略中，端粒​​酶和端粒复合物可能是两种微环境中 HSV-G47Δ 的潜在靶标。