LncRNA-p15135-miR-378a信号轴调节口腔鳞癌糖酵解的功能与机制研究

Although it has been well known that the deregulation of glycolysis could probably lead to the initiation and development of oral squamous cell carcinoma (OSCC), the exact mechanism remains unclear. Our previous studies had suggested that lncRNA-p15135 was significantly increased in the OSCC tissue samples, and miR-378a was significantly decreased. Moreover, the expression of lncRNA-p15135 was correlated with miR-378a expression level. Functional experiment showed that silencing lncRNA-p15135 in OSCC cells could repress both glycolysis and proliferation. A similar effect was observed by increasing miR-378a expression in OSCC cells. Furthermore, there was a predicted binding site of miR-378a on lncRNA-p15135. LncRNA-p15135 expression was significantly repressed when increasing miR-378a in OSCC cells. These results indicated that lncRNA-p15135 might regulate the expression of targeted mRNA of miR-378a by capturing miR-378a in OSCC cells. This interaction might have downstream effects on glycolysis in OSCC cells, which in turn act as the driver for OSCC initiation and development. In this study, we will explore the functional role and mechanisms of lncRNA-p15135-miR-378a signaling axis on glycolysis of OSCC cells. Meanwhile, we will analyze the clinical relevance of lncRNA-p15135 and miR-378a. In summary, this study would uncover the role of lncRNA-miRNA in OSCC glycolysis, and it will provide a novel strategy of diagnosis and treatment of OSCC.

口腔鳞状细胞癌（OSCC）糖酵解异常与OSCC发生发展密切相关，但其具体功能与机制尚不明确。我们前期工作发现：lncRNA-p15135在OSCC癌组织中显著高表达，miR-378a则显著低表达，且两者表达显著相关；沉默lncRNA-p15135或过表达miR-378a可显著抑制OSCC细胞糖酵解及增殖；miR-378a可结合lncRNA-p15135，并对其表达具有明显抑制作用。基于此，我们提出科学假说：lncRNA-p15135通过诱捕miR-378a从而抑制miR-378a对靶mRNA的表达抑制作用，进而共同参与调控OSCC糖酵解，并最终影响OSCC发生发展进程。为验证该假说，本项目将深入阐述lncRNA-p15135-miR-378a信号轴对OSCC糖酵解的具体调控功能、机制及其临床意义。项目将率先揭示lncRNA调控OSCC发生发展新机制，并为OSCC的诊疗提供新思路及理论依据。

口腔鳞状细胞癌是口腔颌面部最常见的恶性肿瘤，其发生发展过程的内在分子机理仍然不明确。最近研究表明，非编码RNA，特别是长链非编码RNA和微小RNA对肿瘤细胞的生长分化、能量代谢、粘附移动、衰老凋亡等整个生命过程起着极其重要的调控作用。然而，其在OSCC发生发展过程中的功能和调控机制尚不清楚。本项目通过细胞-分子-动物-临床水平的实验及分析，发现：. 1. LncRNA-p15135在OSCC癌组织中异常高表达，miR-378a异常低表达。该结果在OSCC细胞系及组织样本中均得到验证。lncRNA-p15135是全长为408bp的，主要定位于OSCC胞浆的长链非编码RNA。. 2. LncRNA-p15135通过影响细胞周期重新分布促进OSCC细胞体外增殖和体内成瘤；miR-378a通过靶向抑制UHRF1表达，调控细胞周期重新分布，从而抑制OSCC细胞体外增殖和体内成瘤。. 3. LncRNA-p15135可直接结合miR-378a，通过诱捕miR-378a，在OSCC细胞中竞争性保护UHRF1的表达，从而调控细胞的生长增殖过程。. 4. LncRNA-p15135、miR-378a及UHRF1在OSCC患者肿瘤组织中的表达水平显著相关，lncRNA-p15135与患者预后情况相关。. 综上，我们明确了lncRNA-p15135通过竞争性保护UHRF1的表达，在OSCC生长增殖过程中起促进作用，并且lncRNA-p15135与OSCC患者临床病理指标相关。通过阐明lncRNA-p15135/miR-378a/UHRF1信号轴调控OSCC生长增殖的作用机制，分析该信号轴与OSCC患者临床病理信息的相关性，为OSCC临床诊断与预后判断提供新的潜在分子标志物与理论基础。