Cancer stem cells (CSCs) contribute to radioresistance in medulloblastoma. Thus, identification of key regulators of medulloblastoma stemness is critical for improving radiotherapy for medulloblastoma. In the present study, we profiled CSC-related long non-coding RNAs (lncRNAs) between radioresistant and parental medulloblastoma cells. The roles of the lncRNA RBM5-AS1 in the stemness and radiosensitivity of medulloblastoma cells were investigated. We found that RBM5-AS1, a novel inducer of medulloblastoma stemness, was significantly upregulated in radioresistant medulloblastoma cells compared to parental cells. Knockdown of RBM5-AS1 diminished the viability and clonogenic survival of both radioresistant and parental medulloblastoma cells after radiation. Silencing of RBM5-AS1 significantly enhanced radiation-induced apoptosis and DNA damage. In vivo studies confirmed that depletion of RBM5-AS1 inhibited tumor growth and increased radiosensitivity in a medulloblastoma xenograft model. In contrast, overexpression of RBM5-AS1 reduced radiation-induced apoptosis and DNA damage in medulloblastoma cells. Mechanistically, RBM5-AS1 interacted with and stabilized sirtuin 6 (SIRT6) protein. Silencing of SIRT6 reduced the stemness and reinforced radiation-induced DNA damage in medulloblastoma cells. Overexpression of SIRT6 rescued medulloblastoma cells from RBM5-AS1 depletion-induced radiosensitization and DNA damage. Overall, we identify RBM5-AS1 as an inducer of stemness and radioresistance in medulloblastoma. Targeting RBM5-AS1 may represent a potential strategy to overcome the resistance to radiotherapy in this malignancy.

中文翻译：

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RBM5-AS1 通过稳定 SIRT6 蛋白促进成神经管细胞瘤的放射抗性

癌症干细胞 (CSC) 有助于成神经管细胞瘤的放射抗性。因此，确定髓母细胞瘤干性的关键调节因子对于改善髓母细胞瘤的放射治疗至关重要。在本研究中，我们分析了抗辐射和亲本成神经管细胞瘤细胞之间的 CSC 相关长非编码 RNA (lncRNA)。研究了 lncRNA RBM5-AS1 在成神经管细胞瘤细胞的干性和放射敏感性中的作用。我们发现与亲本细胞相比，RBM5-AS1 是一种新的髓母细胞瘤干性诱导剂，在抗辐射的髓母细胞瘤细胞中显着上调。RBM5-AS1 的敲低降低了放射抗性和亲本成神经管细胞瘤细胞在放射后的活力和克隆存活率。RBM5-AS1 的沉默显着增强了辐射诱导的细胞凋亡和 DNA 损伤。体内研究证实，RBM5-AS1 的消耗抑制了成神经管细胞瘤异种移植模型中的肿瘤生长并增加了放射敏感性。相比之下，RBM5-AS1 的过度表达减少了成神经管细胞瘤细胞中辐射诱导的细胞凋亡和 DNA 损伤。从机制上讲，RBM5-AS1 与 Sirtuin 6 (SIRT6) 蛋白相互作用并使其稳定。SIRT6 的沉默降低了成神经管细胞瘤细胞的干性并加强了辐射诱导的 DNA 损伤。SIRT6 的过表达从 RBM5-AS1 耗竭诱导的放射增敏和 DNA 损伤中拯救了髓母细胞瘤细胞。总体而言，我们将 RBM5-AS1 确定为髓母细胞瘤干细胞和放射抗性的诱导剂。靶向 RBM5-AS1 可能是克服这种恶性肿瘤放疗耐药性的潜在策略。