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2014 ; 105
(1
): 64-71
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English Wikipedia
Interleukin-6 induces malignant transformation of rat mesenchymal stem cells in
association with enhanced signaling of signal transducer and activator of
transcription 3
#MMPMID24168060
Cui X
; Liu J
; Bai L
; Tian J
; Zhu J
Cancer Sci
2014[Jan]; 105
(1
): 64-71
PMID24168060
show ga
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.