miR-493-5p调控GP73/NF-кB信号抑制肝癌生长与转移的机制研究

MiRNAs are involved in tumor occurrence and development through regulating the expression of their target genes. Our previous studies have shown that the expression of miR-493-5p is significantly decreased in serum and tissues of hepatocellular carcinoma (HCC) patients. Bioinformatics prediction and luciferase activity test further are confirmed the Golgi protein 73 (GP73) is one of the target genes of miR-493-5p. GP73 is highly expressed in HCC, RNA interference GP73 can inhibit NF-kappa B signaling pathway and inhibit the growth and metastasis of HCC cells as well. Based on the preliminary studies, this project plans to further explore the miR-493-5p acting as a potential tumor suppressor on the biological behavior influence on HCC cells, and miR-493-5p inhibiting HCC cell growth and metastasis through the regulation of GP73/NF-kappa B signal pathway. Meanwhile, this project will discuss the potential value of detection of serum miR-493-5p in HCC clinical diagnosis, condition analysis, efficacy evaluation and prognosis. This study is expected to cast a new light on study the molecular mechanism of the pathogenesis of HCC and provide a new target for clinical diagnosis and treatment for HCC.

MiRNAs可通过调控相应靶基因的表达，参与包括肿瘤在内的多种疾病的发生发展。我们前期研究发现，miR-493-5p在肝细胞肝癌（HCC）患者癌组织及血清中表达明显降低；生物信息学预测及荧光素酶活性试验证实高尔基体蛋白73（GP73）是miR-493-5p靶基因之一；GP73在HCC中异常高表达，RNA干扰GP73可抑制NF-кB信号通路，并且抑制HCC细胞的生长与转移。本项目拟在前期研究基础上，进一步探讨miR-493-5p作为一个潜在的抑癌基因对HCC细胞生物学行为的影响；以及其通过调控GP73/NF-кB信号来抑制HCC细胞生长与转移的分子机制。同时，本课题还将探讨血清miR-493-5p检测对HCC临床诊断、病情分析、疗效评估及预后判断中的应用价值。本研究有望为HCC发病的分子机制研究提供新的思路，为HCC的临床诊断与治疗提供新的靶标。

miRNA在HCC的发生发展中发挥着重要的作用。本课题的研究显示，miR-493-5p在HCC患者血清及组织中的表达明显下调，且与HCC患者的肿瘤大小、肿瘤TMN分期紧密相关。过表达miR-493-5p可抑制HCC细胞的增殖，诱导细胞凋亡以及细胞周期G0/G1期阻滞。生物信息学分析和荧光素酶报告试验证明癌基因GP73可作为miR-493-5p一个靶基因。GP73在HCC组织中的高表达与miR-493-5p在HCC组织中的表达水平呈负相关。miR-493-5p可以抑制GP73 mRNA和蛋白质的表达。过表达的GP73可以逆转miR-493-5p介导的抑制HCC细胞的生长增殖，并与NF-kB信号通路的活化有关。本课题研究为HCC发生机制研究提供了新的思路，并为HCC的临床诊断提供新的靶标以及靶向miR-493-5p-GP73轴治疗HCC具有良好的临床应用前景。