Division of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065.
Department of Radiation Oncology, University of California San Francisco, CA, 94143.
Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2203738119. doi: 10.1073/pnas.2203738119. Epub 2022 Sep 6.
Long noncoding RNAs (lncRNAs) play essential roles in the development and progression of many cancers. However, the contributions of lncRNAs to medulloblastoma (MB) remain poorly understood. Here, we identify as an lncRNA enriched in the sonic hedgehog group of MB that is required for maintenance of a treatment-resistant stem-like phenotype in the disease. Loss of results in the differentiation of tumor-initiating, stem-like MB cells and enforces the differentiation of tumorigenic stem-like MB cells into a nontumorigenic state. expression in stem-like MB cells also facilitates treatment resistance by down-regulating p53 signaling and impairing radiation-induced cell death, which can be reversed by therapeutic inhibition of using antisense oligonucleotides. Mechanistically, the RNA binding protein Metadherin (Mtdh), previously linked to resistance to cytotoxic therapy in cancer, binds to in stem-like MB cells. Like the loss of , the loss of reduces tumorigenicity and increases sensitivity to radiation-induced death in stem-like MB cells. Moreover, Miat and Mtdh function to regulate the biogenesis of several microRNAs and facilitate tumorigenesis and treatment resistance. Taken together, these data reveal an essential role for the lncRNA in sustaining a treatment-resistant pool of tumorigenic stem-like MB cells.
长链非编码 RNA（lncRNA）在许多癌症的发生和发展中起着至关重要的作用。然而，lncRNA 对髓母细胞瘤（MB）的贡献仍知之甚少。在这里，我们鉴定出在 Sonic Hedgehog 组 MB 中富集的 lncRNA ，它是维持疾病中治疗抵抗性干细胞样表型所必需的。 的缺失导致肿瘤起始的、干细胞样 MB 细胞的分化，并迫使致瘤性干细胞样 MB 细胞分化为非致瘤性状态。在干细胞样 MB 细胞中表达 也通过下调 p53 信号通路和损害辐射诱导的细胞死亡来促进治疗抵抗，这可以通过使用反义寡核苷酸对 的治疗性抑制来逆转。从机制上讲，先前与癌症中细胞毒性治疗耐药性相关的 RNA 结合蛋白 Metadherin（Mtdh）与 在干细胞样 MB 细胞中结合。与 的缺失一样， 的缺失降低了干细胞样 MB 细胞的致瘤性并增加了对辐射诱导的死亡的敏感性。此外，Miat 和 Mtdh 可调节几种 microRNA 的生物发生，并促进肿瘤发生和治疗抵抗。综上所述，这些数据揭示了 lncRNA 在维持治疗抵抗性肿瘤起始性干细胞样 MB 细胞池中的重要作用。
