LncRNA-B4GALT1-AS1竞争性结合miR-137调控TMED3促进骨肉瘤增殖转移和干性维持的机制研究

骨肉瘤（OS）是儿童和青少年群体中最常见的原发恶性骨肿瘤，预后极差，针对OS尤其是相关干细胞的机制研究仍较少。本课题组发现LncRNA-B4GALT1-AS1对OS增殖转移和干性维持有促进作用，通过mRNA/miRNA高通量测序技术研究其下游调控机制，发现miR-137在肿瘤组织中下调，而TMED3在肿瘤组织中上调且与分期分级和干性相关，TMED3敲减能够显著抑制OS增殖转移，而miR-137和TMED3均未在OS中报道过。因而提出假说LncRNA-B4GALT1-AS1可能通过竞争性结合miR-137调控TMED3，进而促进OS增殖转移和干性维持。在本项目中将通过综合分析LncRNA-B4GALT1-AS1、miR-137和TMED3在临床样本中的表达，并在细胞和动物水平进行建模和验证，该机制的研究将为阐述OS增殖转移和干性维持的分子机制做出贡献，同时为OS的靶向治疗提供潜在的药物靶点。

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents with poor prognosis. However, the mechanism of OS, especially the osteosarcoma stem cells, is still largely unclear. Our previous work found that LncRNA-B4GALT1-AS1 could promote OS proliferation, metastasis and maintenance of stemness. Therefore, in the preliminary experiment of this project, high-throughput sequencing of mRNA/microRNA was used to explore its downstream mechanism. It was verified that miR-137 was down-regulated in cancer tissue, while TMED3 was up-regulated in tumor tissues and related to staging, grading and stemness. Moreover, TMED3 knockdown could significantly inhibit OS progression. Notably, the roles played by miR-137 and TMED3 in OS have rarely been reported. On this basis, we hypothesized that LncRNA-B4GALT1-AS1 may regulate TMED3 through competitively binding miR-137, thus promoting OS progression and stemness maintenance. In this project, we will comprehensively analyze the expression of LncRNA-B4GALT1-AS1, miR-137 and TMED3 in clinical samples, and validate this mechanism at the cellular and animal levels. The completion of this project will contribute to elucidating the molecular mechanism of osteosarcoma development, metastasis and stemness maintenance, and provide potential therapeutic targets for targeted therapy of osteosarcoma.