STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma
STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma
复制标题
DOI：
10.1016/j.canlet.2012.06.006
复制
发表时间：
2012-12-01
期刊：
影响因子：
9.7
通讯作者：
Tang, Ting-Ting
中科院分区：
文献类型：
--
作者：
Tu, Bing;Du, Lin;Tang, Ting-Ting
我们之前证明人间充质干细胞（MSC）促进骨微环境中骨肉瘤的生长。本研究的目的是进一步确定IL-6/STAT3信号对骨肉瘤进展的影响。首先，使用 MSC 的条件培养基在体外刺激骨肉瘤细胞 (Saos-2) 的生长。我们发现 STAT3 被激活，并且这种激活可以被 IL-6 中和抗体阻断。 siRNA或AG490抑制Saos-2细胞中的STAT3可降低细胞增殖、迁移和侵袭，下调Cyclin 0、Bcl-xL和Survivin的mRNA表达并增强细胞凋亡反应。此外，通过将荧光素酶标记的Saos-2细胞注射到胫骨中建立裸鼠骨肉瘤模型，并通过AG490处理小鼠来确定STAT3对肿瘤生长的影响。体内生物发光图像显示 AG490 组的肿瘤生长显着减少。此外，STAT3抑制降低了肺转移率并延长了这些小鼠的生存期。 AG490治疗后，IL-6、p-STAT3和PCNA蛋白水平下降，肿瘤细胞凋亡水平增加。总之，这些数据表明骨微环境中的 MSC 可能促进骨肉瘤的进展，并通过 IL-6/STAT3 信号传导保护肿瘤细胞免受药物诱导的细胞凋亡。 (C) 2012 Elsevier Ireland Ltd. 保留所有权利。
We previously demonstrated that human mesenchymal stem cells (MSCs) promote the growth of osteosarcoma in the bone microenvironment. The aim of the present study was to further determine the effect of IL-6/STAT3 signaling on the progression of osteosarcoma. First, conditioned medium from MSCs was used to stimulate the growth of osteosarcoma cells (Saos-2) in vitro. We found that STAT3 was activated and that the activation could be blocked by an IL-6-neutralizing antibody. The inhibition of STAT3 in Saos-2 cells by siRNA or AG490 decreased cell proliferation, migration and invasion, down-regulated the mRNA expression of Cyclin 0, Bcl-xL and Survivin and enhanced the apoptotic response. Furthermore, a nude mouse osteosarcoma model was established by injecting luciferase-labeled Saos-2 cells into the tibia, and the effect of STAT3 on tumor growth was determined by treating the mice with AG490. In vivo bioluminescence images showed that tumor growth was dramatically reduced in the AG490 group. In addition, STAT3 inhibition decreased the lung metastasis rate and prolonged the survival of these mice. After treatment with AG490, the protein levels of IL-6, p-STAT3 and PCNA were decreased, and the level of apoptosis in the tumor was increased. Altogether, these data indicate that MSCs in the bone microenvironment might promote the progression of osteosarcoma and protect tumor cells from drug-induced apoptosis through IL-6/STAT3 signaling. (C) 2012 Elsevier Ireland Ltd. All rights reserved.