Mesenchymal stem cells (MSCs) can differentiate into chondrogenesis, osteogenesis, myocardium and nerve in specific conditions, but it may undergo malignant transformation when cultivated with tumor cells. This research was to provide preliminary experimental basis for the safe application of MSCs and seek for drugs to avoid the malignant transformation of MSCs in the treatment of tumor. Accordingly, four groups including experimental group, positive control group, negative contrast group and blank group were set. Experimental group was the co-culture group of MSCs and C6 glioma cells. Positive control group was the regular culture group of C6 glioma cells. Negative control group was the co-culture group of MSCs and astrocyte. And blank group was the regular culture group of MSCs. The results showed the expression of IL-6, and IL-6R significantly increased in the group of co-culture with C6; the proliferation situation of MSCs was obviously strengthened; MSCs performed a high expression of GP130, STAT-3, CyclinD1 and BCL-xl, which had statistical significance compared with the contrast group. It can be concluded that the malignant expression of MSCs was related to the overexpression and activation of SIL-R/GP130; and the excessive expression and activation of SIL-6R and GP130 might be one of the important reasons for malignant transformation of MSCs under the microenvironment.