长链非编码RNA Twist1-AS在骨肉瘤中功能及机制研究

Osteosarcoma is the most common bone tumor in young adult. However,the pathogenesis and metastasis mechanism of osteosarcoma still needs to further illustration. Long non-coding RNA (lncRNA) plays important roles in tumor proliferation, apoptosis, invasion and metastasis which to be a potential biomarker and therapeutic target. Based on chip array data, we found that levels of Twist1 and Twist1 natural antisense (Twist1-AS, one of the lncRNAs) were increased significantly in osteosarcoma tissues compared to paired normal adjacent tissues. Importantly, we also demonstrated that Twist1-AS can promote invasion and metastasis of osteosarcoma cells. In current study, we want to figure out the mechanism of stabilizing Twist1 mRNA by Twist1-AS.What's more, we will try to reveal the mechanism of the function of Twist1 and Twist1-AS on osteosarcoma cell proliferation, invasion and metastasis. We will also find the correlation between level of Twist1/Twist1-AS and histopathologic grades and prognosis of osteosarcoma. The research will help us to understand the functional roles of Twist1-AS and Twist1 in tumorigenesis of osteosarcoma. It will provide a new strategy for diagnosis and therapy for osteosarcoma.

骨肉瘤是最常见的恶性骨原发肿瘤，发病和转移机制有待研究。长链非编码RNA（lncRNA）可参与肿瘤的生长、凋亡调控、浸润与转移等过程，有望成为新型标志物和治疗靶点。基于前期结果，我们发现Twist1基因内源性的反义转录产物（Twist1-AS，lncRNA的一种）在骨肉瘤组织相对癌旁组织出现显著表达上调。前期体外实验证实Twist1-AS具有调节骨肉瘤细胞迁移侵袭的功能。并证实Twist1-AS可正向调节Twist1及其信号通路。本项目中，我们将阐明Twist1-AS稳定Twist1 mRNA的具体作用机理；深入研究Twist1-AS对骨肉瘤细胞增殖、转移的影响及相关分子机制；建立Twist1-AS的表达水平与骨肉瘤病理分级、治疗效果之间的相关性。阐明Twist1-AS在骨肉瘤发生、发展中的作用机制，发现潜在的治疗靶标和诊断的生物标志物，有望为骨肉瘤的临床诊断和治疗提供新策略和方法。

骨肉瘤是最常见的恶性骨原发肿瘤，发病和转移机制有待研究。长链非编码 RNA（lncRNA）可参与肿瘤的生长、凋亡调控、浸润与转移等过程，我们发现Twist1 基因内源性的反义转录产物Twist1-AS（lncRNA的一种）的存在，其在骨肉瘤组织的表达相对癌旁组织出现显著表达上调。同时体外实验证实Twist1能够促进骨肉瘤细胞的增殖、迁移和侵袭，而其反义转录产物 Twist1-AS 同样具有调节骨肉瘤细胞增殖迁移侵袭的功能。有意思的是，两者的表达成正相关，即Twist1AS能够调节Twist 1的表达水平。而且能影响其下游信号通路。本项目中，首先发现了Twist 1-Twist1-AS调节环路的存在，并证明其在骨肉瘤发生、发展中的作用机制，有可能为骨肉瘤的发病机制提供新的理论依据和新的治疗靶点。