miR-129-5p 靶向调控VCP抑制成骨骨肉瘤侵袭转移

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. The development of Lung metastasis is the main cause of death in patients with OS. How to improve the efficacy of osteosarcoma patients with lung metastasis is a major issue. The study on miRNAs has provides a new idea for the diagnosis and treatment of osteosarcoma. Various studies revealed that miR-129-5p is expressed at low level in a variety of human tumors, and increase its expression could effectively inhibit cell proliferation. However, whether miR-129 involves in OS metastasis and the underlying molecular mechanism had not been reported. We found that the up-regulation of miR-129-5p has been shown to inhibit VCP expression in osteosarcoma cells, and miR-129-5p is likely targeting VCP. That VCP promotes the metastasis of osteosarcoma via regulating NF-KB has been confirmed by various studies. Therefore, we hypothesized that miR-129-5p inhibits the OS cells proliferation and metastasis by targeting VCP. In this study, the effect of miR-129 expression on OS cell invasion and lung metastasis will be investigated in OS cell line and nude mice, also the molecular mechanism of miR-129-5p on OS cell proliferation and metastasis through down-regulation of VCP will be investigated, and it may serve as a therapeutic target.

骨肉瘤（OS）在原发恶性骨肿瘤中占据首位，肺部转移是死亡最主要原因。因此，深入研究骨肉瘤转移分子机制，为骨肉瘤转移的防治具有重要意义。我们前期研究发现VCP表达水平与骨肉瘤肺部转移有显著的正相关，并且RNAi沉默VCP能有效的抑制骨肉瘤细胞体外侵袭、增殖。同时，我们发现miR-129-5p分子表达水平在不同侵袭转移能力的骨肉瘤细胞株中存在显著差异，而它恰是我们通过生物信息学预测的可能调控VCP基因的分子。本研究试图证明VCP基因的高表达促进骨肉瘤细胞侵袭转移，并且miR-129-5p的低表达是骨肉瘤细胞上调VCP基因表达的新分子机制；进一步通过体外侵袭迁徙实验和裸鼠体内实验，检测has-miR-129-5p分子对骨肉瘤细胞迁徙转移能力的影响，探索应用miR-129-5p抗骨肉瘤侵袭转移的可能性。

骨肉瘤（OS）在原发恶性骨肿瘤中占据首位，肺部转移是死亡最主要原因，近几十年来全球的骨肉瘤患者总体5年生存率仍然徘徊不前，因此，深入研究骨肉瘤转移分子机制，对骨肉瘤转移的防治具有重要意义。本研究中我们发现：（1）VCP蛋白在骨肉瘤组织中呈高表达，并且其表达水平与骨肉瘤肺部转移密切相关；（2））VCP高表达激活PI3K/AKT/NF-κβ信号通路促进骨肉瘤细胞侵袭转移；（3）miR-129-5p能负向调控VCP表达并抑制骨肉瘤细胞迁徙和侵袭；（4））甲基化修饰是miR-129-5p在骨肉瘤细胞中低表达的调控机制之一；（5）miR-129-5p调控骨肉瘤裸鼠体内生长。