Interleukin-6 induces malignant transformation of rat mesenchymal stem cells in association with enhanced signaling of signal transducer and activator of transcription 3.
Interleukin-6 induces malignant transformation of rat mesenchymal stem cells in association with enhanced signaling of signal transducer and activator of transcription 3.
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DOI：
10.1111/cas.12313
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发表时间：
2014-01
期刊：
影响因子：
5.7
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Cui X;Liu J;Bai L;Tian J;Zhu J
间充质干细胞（MSCs）有潜力成为细胞治疗的来源。然而，间充质干细胞可以在高水平白细胞介素(IL)-6存在的肿瘤微环境中发生恶性转化。在本研究中，我们研究了IL-6和转录3信号传导器（STAT3）在MSCs恶性转化中的作用。分离大鼠间充质干细胞并与C6胶质瘤细胞间接共培养。以MSCs与星形胶质细胞共培养为对照。培养7天后，采用MTT法和免疫荧光染色检测细胞的恶性转化情况。采用RT-PCR、ELISA和Western blot检测培养细胞和条件培养基中肝细胞生长因子、IL-6、碱性成纤维细胞生长因子的水平，STAT3和可溶性IL-6受体的表达。同时测定STAT3下游靶点CyclinD1和Bcl-xl的表达水平。我们的数据显示，几乎所有的MSCs在与胶质瘤细胞间接共培养后都变成了表型恶性，当这些细胞注射到裸鼠体内时，通过肿瘤形成实验证实了这一点。与胶质瘤细胞共培养的MSCs中IL-6的表达显著升高，与可溶性IL-6受体、跨膜糖蛋白GP130、STAT3、磷酸化STAT3、CyclinD1、Bcl-xl的表达显著升高有关。用IL-6处理MSCs时，获得了类似的结果。用STA-21处理共培养的MSCs和胶质瘤细胞，阻断构成性STAT3信号传导，降低了肿瘤微环境中MSC肿瘤样转化的风险。这些数据表明，IL-6在大鼠间充质干细胞的恶性转化中起着关键作用，这与肿瘤微环境中STAT3信号通路的增强有关。
Mesenchymal stem cells (MSCs) have the potential to be the source for cell-based therapies. However, MSCs can undergo malignant transformation in a tumor microenvironment where a high level of interleukin (IL)-6 is present. In this study, we investigated the role of IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling in malignant transformation of MSCs. Rat MSCs were isolated and indirectly cocultured with C6 glioma cells. Coculture of MSCs with astrocytes was used as a control. After 7 days of culture, the cells were assessed for malignant transformation using MTT assay and immunofluorescence staining. The levels of hepatocyte growth factor, IL-6, and basic fibroblast growth factor, and the expression of STAT3 and soluble IL-6 receptor in the cultured cells and conditioned media were measured using RT-PCR, ELISA, and Western blot analysis. The expression levels of STAT3 downstream targets, CyclinD1 and Bcl-xl, were determined as well. Our data showed that almost all of the MSCs became phenotypically malignant after indirect coculture with glioma cells, which was confirmed by tumor formation assays when these cells were injected into nude mice. The expression of IL-6 was significantly increased in MSCs cocultured with glioma cells, which was associated with significantly increased expressions of soluble IL-6 receptor, transmembrane glycoprotein GP130, STAT3, phosphorylated STAT3, CyclinD1, and Bcl-xl. Similar results were obtained when the MSCs were treated with IL-6. Treatment of the cocultured MSCs and glioma cells with STA-21, to block the constitutive STAT3 signaling, reduced the risk of MSC tumor-like transformation in the tumor microenvironment. These data suggest that IL-6 plays a critical role in malignant transformation of rat MSCs, which is associated with an enhancement of the STAT3 signaling pathway in the tumor microenvironment.
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DOI：
10.1158/1078-0432.ccr-08-3252
发表时间：
2009-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Knowles LM;Stabile LP;Egloff AM;Rothstein ME;Thomas SM;Gubish CT;Lerner EC;Seethala RR;Suzuki S;Quesnelle KM;Morgan S;Ferris RL;Grandis JR;Siegfried JM
通讯作者：
Siegfried JM
影响因子：
50.3
作者：
Bromberg J;Wang TC
通讯作者：
Wang TC
影响因子：
6.2
作者：
WESTERMANN, R;UNSICKER, K
通讯作者：
UNSICKER, K
影响因子：
11.2
作者：
Rosland, Gro Vatne;Svendsen, Agnete;Schichor, Christian
通讯作者：
Schichor, Christian
大鼠骨髓间充质干细胞与肿瘤细胞间接共培养发生恶性转化
影响因子：
3.6
作者：
Liu, Jianping;Zhang, Yalan;Zhu, Jing
通讯作者：
Zhu, Jing