滑膜肉瘤融合基因SYT-SSX1/2靶基因的筛选及功能鉴定

Synovial sarcoma is a highly invasive malignant tumor derived from bone marrow mesenchymal stem cells. More than 95% of synovial sarcoma is characterized by the t(X;18)(p11.2;q11.2) chromosomal translocation which always represents the fusion SYT with SSX. Because the molecular mechanism of fusion gene in synovial sarcoma remains poorly understood, the lack of specific targeting drug therapy, the current operation excision, chemotherapy and radiotherapy are the main treatment measures of the synovial sarcoma. In previous studies we found that the synovial sarcoma patients of SYT-SSX1 had the bigger tumor volume and poorer clinical prognosis compared with that of SYT-SSX2. At the same time, we confirmed that the cells with SYT-SSX1-positive showed stronger ability of proliferation and metastasis. Based on the above results, the project intends to use high-throughput RNAi screening platform, screening and identification of target genes which affected synovial sarcoma growth and metastasis. Through animal experiments and clinical sample analysis, we obtain the target genes which are important for synovial sarcoma targeted therapy and individual therapy.

滑膜肉瘤是源于骨髓间充质干细胞的一种高度恶性肿瘤，95%以上的滑膜肉瘤具有特异性的染色体异位，形成融合基因SYT-SSX。由于对于融合基因在滑膜肉瘤中的分子机制仍然知之甚少，缺乏特异的靶向治疗药物，目前手术切除为主，辅助放疗和/或阿霉素为基础的化疗是当前滑膜肉瘤的主要治疗措施。在我们的既往研究中发现SYT-SSX1和SYT-SSX2在滑膜肉瘤中具有不同的临床意义和生物学功能：表达SYT-SSX1基因的滑膜肉瘤患者的瘤体体积更大，临床预后也较差；同时在细胞水平上也证实了过表达SYT-SSX1的细胞具有更强的增殖能力、平板克隆形成能力和转移能力。基于上述研究结果，本项目拟采用高通量RNAi筛选平台，筛选并鉴定影响滑膜肉瘤生长和转移的关键基因，最终经过前期Micro-RNA芯片结果，动物实验和临床样本验证分析多重验证，得到调控滑膜肉瘤发生发展的靶基因，从而为滑膜肉瘤的靶向治疗和个体化治疗奠定基础

滑膜肉瘤是起源于骨髓间充质干细胞的一种高度恶性肿瘤，95%以上的滑膜肉瘤具有特异性的染色体异位，形成融合基因SYT-SSX。由于对于融合基因在滑膜肉瘤中的分子机制仍然知之甚少，缺乏特异的靶向治疗药物，目前手术切除为主，辅助放疗和/或阿霉素为基础的化疗是当前滑膜肉瘤的主要治疗措施。在本项目中，通过Micro-RNA 芯片筛选和验证，发现PD-1通路在滑膜肉瘤的发生发展中发挥着重要的作用，并是通过两条途径来发挥作用的，PD-L1高表达本身促进肿瘤作用和PD-L1高表达引起的免疫逃逸的双重因素。目前在国内外文献中未见报道，在后续工作，将进一步明确PD1通路和滑膜肉瘤融合基因之间的相关性及其中的分子机制，为滑膜肉瘤靶向治疗和免疫治疗提供分子生物学基础。