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

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.

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。

多发性骨髓瘤（MM）难以治疗以及常见耐药机制，主要系其骨髓微环中骨髓间充质干细胞和克隆性浆细胞之间的旁分泌途径，为MM细胞定位、黏附和生长提供庇护。SRC-3是既是p160类固醇受体共激活因子家族蛋白，又是一个原癌扩增因子，参与多个核受体及其它转录因子的激活，通过多个途径参与细胞增殖与凋亡。Src-3基因剔除小鼠存在生长发育迟缓、身材矮小，血清IGF-1水平偏低，同时对放射的敏感性增加等特性。这些结果提示SRC-3可能改变MM的骨髓微环境参与MM的发生发展。 . 本研究证明SRC3敲除的BM-MSCs在生长特性、分泌细胞因子水平和粘附性方面均显著低于wild-type mice，证明SRC-3基因通过影响BM MSCs特性从而影响骨髓微环境。进而把SRC-3敲除小鼠MSCs与MM细胞直接/间接共同培养，发现MSC细胞的分泌、粘附，成骨等特性改变后抑制小鼠MM细胞的增殖，增加其凋亡。另外，研究还发现MM患者体内SRC3及其下游蛋白Cx43高表达，SRC3通过调节下游因子Cx43的表达从而抑制MAPK通路的机制，达到抑制骨髓瘤细胞增殖作用。因此，SRC-3可作为一个分子靶点通过干扰骨髓微环境从而达到抑制多发性骨髓瘤细胞增殖的作用.