SRC-3基因敲除的骨髓间充质干细胞对抑制多发性骨髓瘤的作用

项目名称： SRC-3基因敲除的骨髓间充质干细胞对抑制多发性骨髓瘤的作用

项目编号： No.81500175

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 金婕

作者单位： 中国人民解放军第三军医大学

项目金额： 18万元

中文摘要： 多发性骨髓瘤（MM）难以治疗，其特征是恶性浆细胞在骨髓中的克隆增殖。已知骨髓微环境，尤其是骨髓间充质干细胞和克隆性浆细胞之间的旁分泌途径，是MM细胞定位、黏附和生长所必需，可保护MM细胞免受化疗杀伤，在骨髓微环境的维持与MM发病机制中起重要作用。SRC-3是p160类固醇受体共激活因子家族蛋白，可与核受体及其它转录因子作用来调节转录。SRC-3在多种癌症中过表达，与癌症增殖、转移、复发和化疗耐药相关。我们的前期结果表明，在放射等外部压力下SRC-3对正常骨髓细胞存活相当重要，Src-3基因剔除小鼠对放射的敏感性增加。这些结果提示SRC-3可能参与维持MM生长所需的骨髓微环境。本研究为前期研究的延伸，旨在明确骨髓间充质干细胞表达SRC-3是否促进MM细胞的增殖和存活，并且在实验动物中测试移植Src-3-/-骨髓间充质干细胞是否能抑制MM发展，为治疗多发性骨髓瘤的新方法提供临床前期的理论基础。

中文关键词： 多发性骨髓瘤；骨髓间充质干细胞；类固醇受体共激活因子-3；基因敲除；基因敲除

英文摘要： 　Multiple myeloma (MM) is a hard-to-treat disease which is characterized by the clonal proliferation of malignant plasma cells in the bone marrow. The bone marrow microenvironment, especially bone marrow-derived mesenchymal stem cells, has been shown to play crucial roles in MM pathogenesis. Paracrine circuits between BM-MSCs and clonal plasma cells provide essential signals for MM cell localization, adhesion, and growth. Moreover, BM-MSCs have been shown to protect MM cells from chemotherapy. SRC-3 is a p160 steroid receptor coactivator family protein which regulates transcription by interacting with nuclear receptors and other transcription factors. SRC-3 overexpression has been found in various cancers, including breast, pancreatic, ovarian, gastric, prostate, liver, endometrial, lung cancers, and colorectal carcinoma. High levels of SRC-3 have been shown to be associated with cancer proliferation, metastasis, recurrence, and chemoresistance. We and others have shown previously that SRC-3 plays a role in cell survival under external stress, such as chemical and radiation assaults. We further showed that Src-3−/− mice are sensitive to -irradiation, and have reduced proliferation and increased apoptosis of bone marrow nucleated cells. These results suggest that SRC-3 may participate in the maintenance of the bone marrow microenvironment required for MM progression. This proposal is an extension of our previous studies, and the goal is to determine whether the expression of SRC-3 in BM-MSC is involved in supporting the proliferation and survival of MM cells. Transplant of Src-3−/− BM-MSCs will be tested in an MM mouse model to determine its possible therapeutic effect on inhibiting MM progression in vivo. The results obtained from this study will provide preclinical support for targeting SRC-3 as a possible treatment against multiple myeloma.

英文关键词： Multiple myeloma;Bone marrow-derived mesenchymal stromal cells;SRC-3;bone marrow microenvironment;gene knock-out