LincRNA-Cox2/EGR1在椎板切除术后硬膜外瘢痕形成中的调节作用及机制研究

Epidural scar formation after laminectomy remarkably weakens the effects of decompression. Preventing or reducing epidural scar makes a big difference. Our previous study has demonstrated that EGR1, a transcription factor, was significantly associated with responsiveness to TGF-β stimulation in fibroblasts and plays a vital role in regulating scar formation. However, upstream molecular mechanism of EGR1 remains unclear. To investigate the potential mechanism, we performed microarray analysis regarding non-coding RNAs. Results showed that lincRNA-Cox2 was negatively correlated with level of EGR1. Further, we established scar model after laminectomy in mice and found that lincRNA-Cox2 was negatively correlated with scar severity. Based on these findings, we hypothesized that lincRNA-Cox2 regulates scar formation via downregulating EGR1. The purpose of the present study was 1）to validate the correlation between lincRNA-Cox2 and scar formation at human tissue level; 2) to explore the potential molecular mechanism involving lincRNA-Cox2 to EGR1; 3) to investigate the feasibility of preventing or reducing epidural scar via targeting lincRNA-Cox2. This research will uncover the mechanism of scar formation from a new insight and provide new thoughts in solving this clinical problem.

椎板切除术后硬膜外瘢痕粘连严重影响了手术减压的效果,因此有效预防或减少硬膜外瘢痕粘连意义重大。我们的前期研究发现转录因子EGR1与成纤维细胞对TGF-β刺激的反应性有关 ，从而在瘢痕形成中起到重要调节作用，然而其上游机制尚不明确。为了明确调节EGR1表达的分子机制，我们进行了LncRNA差异基因筛选，发现lincRNA-Cox2表达与EGR1呈显著负相关 ，随后我们在椎板切除术小鼠模型中证实其表达与瘢痕严重程度呈负相关。据此，我们推测lincRNA-Cox2通过调控EGR1，从而调节瘢痕形成。本课题1）在人体组织水平进一步验证lincRNA-Cox2与瘢痕以及EGR1的关系；2）研究lincRNA-Cox2下调EGR1的具体分子机制；3）探讨lincRNA-Cox2作为靶点防治硬膜外瘢痕粘连的可行性。本项目的完成可从新的角度揭示瘢痕粘连形成的机制，为解决这一临床难题提供新思路和新靶点

椎板切除术后硬膜外瘢痕粘连严重影响了手术减压的效果,因此有效预防或减少硬膜外瘢痕粘连意义重大。本课题研究发现：椎板切除术后硬膜外组织和活化的纤维化成纤维细胞中LncRNA-COX2 显着降低。在体外，LncRNA-COX2 的过表达通过抑制成纤维细胞分化、增殖和迁移来抑制硬膜外纤维化。从机制上讲，LncRNA-COX2 作为EGR1的竞争性内源性RNA(ceRNA) 发挥作用。LncRNA-COX2的上调显着降低了EGR1的表达并显示出抗纤维化作用，而LncRNA-COX2被抑制表达后EGR1显着上调。在体内，LncRNA-COX2 减轻了小鼠椎板切除术诱导的硬膜外纤维化。综上所述，结果表明 LncRNA-COX2 通过靶向EGR1显示出抗纤维化作用，并将LncRNA-COX2鉴定为预防异常硬膜外纤维化的治疗分子。本课题研究从新的角度揭示了瘢痕粘连形成的机制，为解决这一临床难题提供了新思路和新靶点。