miR-143/HDAC7 pathway 通过调控组蛋白乙酰化改变影响骨肉瘤转移特性的分子机制研究

骨肉瘤早期转移是影响临床预后的关键因素，转移发生分子机制受广泛关注，组蛋白去乙酰化酶在肿瘤转移中的调控作用及其机制值得深入研究。本项目组在前期研究中发现了microRNA miR-143可以显著影响骨肉瘤细胞迁移能力，进一步研究发现该microRNA可以靶向调控HDAC7，且HDAC7过表达可以补救miR-143对迁移能力的影响，提示miR-143/HDAC7 pathway可能在骨肉瘤转移中发挥重要作用。本项目组拟首先通过基因过表达和干扰、细胞迁移和侵蚀能力检测、小动物活体成像等技术在体内外充分验证miR-143/HDAC7对骨肉瘤的迁移能力的影响，并进一步利用ChIP-on-chip技术分析miR-143通过HDAC7影响的特异性组蛋白乙酰化位点，从而系统地探讨microRNA及组蛋白乙酰化酶协同调控骨肉瘤转移的新的表观遗传学机制，并为骨肉瘤的临床诊断和分子靶向治疗提供新的研究靶点。

The development of early metastasis is the major cause of death in osteosarcoma, and the mechanisms that orchestrate the multiple oncogenic insults required for metastatic activity of osteosarcoma are urgent in current studies. To date, epigenetic regulation, for example, histone acetylation has been suggested to participate in osteosarcoma development. However, we are still at the beginning of revealing the roles of histone deacetylases in osteosarcoma carcinogenesis and progression. Here, we focused on the roles of histone deacetylase (HDAC) 7, which is an important regulator of histone acetylation and epigenetic modification, in metastatic osteosarcoma. In our previous study， we found miR-143 was down-regulated in osteosarcoma cell lines and primary tumor samples, and the restoration of miR-143 reduced cell viability, promoted cell apoptosis and suppressed metastatic activity. Interestingly, we found that HDAC7 was over-expressed in metastatic osteosarcoma, and HDAC7 identified to be a potential novel target of miR-143. Additionally, And the overexpression of HDAC7 CDS without 3'UTR region partly rescued the influence of miR-143 on the osteosarcoma cell line U2OS. In our current proposal, we plan to test the hypothesis that the miR-143 regulates the metastatic ability of osteosarcoma cell lines through a HDAC7-dependent manner. Then we try to scan for the specific histone acetylation sites in the osteosarcoma cells genome and investigate their roles in osteosarcoma metastasis. Thus, our current proposal may find a novel mechanism of osteosarcoma metastasis through a mir-143/HDAC7 pathway and indicate its potential application in cancer therapy.