Osteosarcoma is one of the most frequent common primary malignant tumors in childhood and adolescence. Long non-coding RNAs (lncRNAs) have been reported to regulate the initiation and progression of tumors. However, the exact molecular mechanisms involving lncRNA in osteosarcomagenesis remain largely unknown. Li-Fraumeni syndrome (LFS) is a familial cancer syndrome caused by germline p53 mutation. We investigated the tumor suppressor function of lncRNA H19 in LFS-associated osteosarcoma. Analyzing H19-induced transcriptome alterations in LFS induced pluripotent stem cell (iPSC)-derived osteoblasts, we unexpectedly discovered a large group of snoRNAs whose expression was significantly affected by H19. We identified SNORA7A among the H19-suppressed snoRNAs. SNORA7A restoration impairs H19-mediated osteogenesis and tumor suppression, indicating an oncogenic role of SNORA7A. TCGA analysis indicated that SNORA7A expression is associated with activation of oncogenic signaling and poor survival in cancer patients. Using an optimized streptavidin-binding RNA aptamer designed from H19 lncRNA, we revealed that H19-tethered protein complexes include proteins critical for DNA damage response and repair, confirming H19's tumor suppressor role. In summary, our findings demonstrate a critical role of H19-modulated SNORA7A expression in LFS-associated osteosarcomas.

骨肉瘤是儿童和青少年时期最常见的常见原发性恶性肿瘤之一。据报道，长的非编码RNA（lncRNA）调节肿瘤的发生和发展。但是，在骨肉瘤发生中涉及lncRNA的确切分子机制仍是未知之数。Li-Fraumeni综合征（LFS）是由种系p53突变引起的家族性癌症综合征。我们调查了LFS相关骨肉瘤中lncRNA H19的肿瘤抑制功能。分析LFS诱导的多能干细胞（iPSC）来源的成骨细胞中H19诱导的转录组变化，我们意外地发现了一大批snoRNA，其表达受H19显着影响。我们在H19抑制的snoRNAs中鉴定出SNORA7A。SNORA7A修复会损害H19介导的成骨和肿瘤抑制，提示SNORA7A具有致癌作用。TCGA分析表明SNORA7A表达与致癌信号的激活和癌症患者的不良生存有关。使用从H19 lncRNA设计的优化的抗生蛋白链菌素结合RNA适体，我们揭示了H19束缚的蛋白质复合物包括对DNA损伤反应和修复至关重要的蛋白质，证实了H19的肿瘤抑制作用。总而言之，我们的发现证明了H19调节的SNORA7A表达在LFS相关的骨肉瘤中的关键作用。我们发现，H19系留的蛋白质复合物包括对DNA损伤反应和修复至关重要的蛋白质，证实了H19的抑癌作用。总而言之，我们的发现证明了H19调节的SNORA7A表达在LFS相关的骨肉瘤中的关键作用。我们发现，H19系留的蛋白质复合物包括对DNA损伤反应和修复至关重要的蛋白质，证实了H19的抑癌作用。总而言之，我们的发现证明了H19调节的SNORA7A表达在LFS相关的骨肉瘤中的关键作用。