IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling

Mesenchymal stem cells (MSCs) hold great promise as potential therapies for tumors through the delivery of various anticancer agents. However, exogenous tissue-derived MSCs, such as those of bone marrow, have exhibited a tendency for malignant transformation in the tumor microenvironment. This issue remains controversial and is poorly understood. In the present study, the role of interleukin 22 (IL22)/IL22 receptor subunit α 1 (IL22RA1) and signal transducer and activator of transcription 3 (STAT3) signaling in the malignant transformation of MSCs was investigated. Following isolation of rat MSCs and their indirect co-culture with C6 glioma cells, the transformed MSCs exhibited tumor cell characteristics. The Cancer Genome Atlas-Glioblastoma Multiforme analysis revealed that primary and recurrent glioblastomas have increased IL22RA1 expression, compared with normal tissues, whereas the expression of IL22 was low in glioblastoma and normal tissues. mRNA and protein expression levels of IL22RA1 were significantly increased in the MSCs co-cultured with C6 glioma cells. Furthermore, MSCs incubated with IL22 exhibited increased proliferation, migration and invasion. STAT3 demonstrated activation and nuclear translocation in the presence of IL22. Additionally, STAT3 small interfering RNA significantly inhibited the migration and invasion ability of MSCs, and the expression of the STAT3 downstream targets cyclin D1 and B-cell lymphoma-extra large under IL22 stimulation, indicating that IL22 also promoted MSC migration and invasion through STAT3 signaling. These data indicated that IL22 serves a critical role in the malignant transformation of rat MSCs, which is associated with an enhancement of the IL22RA1/STAT3 signaling pathway in the tumor microenvironment.