长链非编码RNA Linc02076影响卵巢癌转移和预后的机制研究

Alternative splicing is an important pattern for long non-coding RNA (LncRNA) to exactly regulate the function of coding-genes, which is closely related to malignancies. Our preliminary study indicated that the expression of Linc02076 in metastasis tissues of ovarian cancer was significantly higher than that in the primary tumor tissues. Further studies showed that the lncRNA might be involved in the ATM gene alternative splicing, resulting in the formation of truncated ATM-v2 variants that could associate with RASAL2 to function in downstream pathways. Accordingly, we hypothesized that this lncRNA could influence the metastasis of ovarian cancer through regulating ATM gene alternative splicing characteristically. Here, in this project we plan to test the association between Linc02076 and ovarian cancer metastasis as well as prognosis by detecting the LncRNA expression in clinical large samples. To investigate the molecular mechanism of Linc02076 in ovarian cancer metastasis, a series of cell lines carrying different expression of Linc02076 will be constructed via lentivirus technique, and a series of functional assays will be further implemented in vitro and in vivo. This project will help to clarify the pathological mechanism, and provide scientific evidences for targeted therapy of ovarian cancer.

可变剪接是长链非编码RNA（LncRNA）精细调控编码基因功能的重要方式，与肿瘤关系密切。课题组前期预实验发现Linc02076在卵巢癌转移组织中的表达显著高于其原发灶；该LncRNA可能参与了ATM基因的可变剪接，且促成的截断型ATM剪接体可以与RASAL2结合以此作用于下游信号通路。据此，我们假设该LncRNA可以通过调控ATM基因可变剪接的方式影响卵巢癌的转移和预后。本项目拟利用临床大样本检测该LncRNA的表达，分析其与卵巢癌转移和预后的关联；通过构建过表达和沉默Linc02076的模式细胞系，联合体内-体外等实验方法系统揭示该LncRNA在卵巢癌转移中的作用及生物学实质，为卵巢癌病理机制的阐明、靶向治疗提供科学依据。

非编码RNA在生命调控过程中扮演重要角色，与恶性肿瘤发生发展密切相关。剖析其在肿瘤进展中的功能作用及内在机制，对肿瘤的科学防治具有重要的应用意义。本研究旨在探索长链非编码RNA LINC02076与我国人群卵巢癌临床转移及生存预后的关系及其分子机制。结果发现LINC02076表达与卵巢癌临床转移与生存结局存在显著关联，是卵巢癌临床靶向治疗及预后评估的一个潜在生物标志物。LINC02076在卵巢癌转移组织及处于晚期患者的组织中呈高表达状态，发挥着促癌转移的功能作用，其沉默表达可显著抑制卵巢癌细胞系的迁移、侵袭及裸鼠肿瘤生长与体内转移，而过表达LINC02076后则起着明显促进细胞转移的相反作用。系列分子生物学试验提示LINC02076与不均一核糖核蛋白A1(HNRNPA1)结合，影响下游靶基因的可变剪切进而导致卵巢癌的临床转移。本研究为卵巢癌的基础研究和临床靶向治疗提供了新的思路和分子靶标。