LncRNA-骨肉瘤相关转录子1（OSAT1）通过竞争性抑制miRNA-661促进OS恶性进展的分子机制研究

Osteosarcoma (OS) is the most common malignant bone tumor, and it’s in dire need of new diagnostic methods and treatments due to its poor prognosis. Recently, lncRNA has been proved to play an important role in regulation of the malignant biological behavior of osteosarcoma including proliferation, invasion and metastasis. Previous research of our group had noticed an overexpression of lncRNA OSAT1 in tissue sample of OS patients. Down-regulating OSAT1 could lead to inhibition of OS cell proliferation and the effect was significantly related to MAML, a co-activator of Notch and Wnt/β-catenin signaling pathway. Meanwhile, we had proved a tumor suppression effect of miRNA-661 on OS, which also related to MAML. Preliminary experiment showed that OSAT1 could combine with miRNA-661. Hereby, we speculated that OSAT1 could cancel the down-regulation effect of MAML caused by miRNA-661, and eventually regulate OS development through Notch and Wnt/β-catenin signaling pathway. With OSAT1 overexpression and silencing cells and animal models, the relation between OSAT1 and miRNA-661, as well as their molecular mechanism regulating MAML to infect the development of OS is studied in this project. As a potential biological target influencing the malignant biological behavior of OS, OSAT1 may have important value on early diagnosis and targeted therapy of OS. It may also fundamentally improve prognosis of OS patients by providing a new method on diagnosis and treatment.

骨肉瘤（OS）是最常见的恶性骨肿瘤，预后极差，亟需新的生物诊疗手段。近年发现LncRNA在OS增殖、侵袭、转移等恶性行为中起关键作用。课题组研究发现LncRNA-OSAT1在OS患者瘤组织中高表达，下调其表达后瘤细胞增殖受抑且与Notch和Wnt/β-catenin通路共活化物MAML显著相关；同时课题组发现miR-661具有抑制OS增殖的作用，且亦与MAML相关。据此推测OSAT1可能通过淬灭miR-661（预实验证实两者可特异性结合），解除miRNA-661对MAML表达的抑制，经Notch和Wnt通路影响OS发展。本研究拟通过OSAT1过表达和沉默细胞及动物模型，深入研究OSAT1与miRNA-661关系及其调控MAML进而影响OS发展的分子机制。OSAT1作为影响OS恶性行为的重要节点，具早期诊断和靶向治疗OS的巨大潜在价值，有望为OS生物诊疗提供新途径并从根本上改善OS患者预后。

研究背景：骨肉瘤（OS）是最常见的恶性骨肿瘤，预后极差，亟需新的生物诊疗手段。近年发现LncRNA在OS增殖、侵袭、转移等恶性行为中起关键作用。课题组研究发现LncRNA-OSAT1在OS患者瘤组织中高表达，下调其表达后瘤细胞增殖受抑且与Notch和Wnt/β-catenin通路共活化物MAML显著相关；同时课题组发现miR-661具有抑制OS增殖的作用，且亦与MAML相关。据此推测OSAT1可能通过淬灭miR-661（预实验证实两者可特异性结合），解除miRNA-661对MAML表达的抑制，经Notch和Wnt通路影响OS发展。.研究内容：本研究通过OSAT1过表达和沉默细胞及动物模型，深入研究OSAT1与miRNA-661关系及其调控MAML进而影响OS发展的分子机制。1. OSAT1通过MAML1、MAML3促进骨肉瘤细胞增殖和转移；2. miRNA-661分别与OSAT1和MAML特异性结合的研究；3. OSAT1竞争性结合miRNA-661，经由Notch和Wnt/β-catenin通路调控骨肉瘤恶性进展的研究.结论及意义：.确定OSAT1在各骨肉瘤细胞系中的表达，并阐明了OSAT1对骨肉瘤恶性生物行为调控的分子机制。构建OSAT1及MAML突变载体，确定与miRNA-661的结合位点。OSAT1作为影响OS恶性行为的重要节点，具早期诊断和靶向治疗OS的巨大潜在价值，有望为OS生物诊疗提供新途径并从根本上改善OS患者预后。