Abstract
Glioma stem cells (GSCs) exhibit stem cell properties and high resistance to radiotherapy. The main aim of our study was to determine the roles of ROS in radioresistance and stemness of GSCs. We found that microRNA (miR)-153 was down-regulated and its target gene nuclear factor-erythroid 2-related factor-2 (Nrf-2) was up-regulated in GSCs compared with that of non-GSCs glioma cells. The enhanced Nrf-2 expression increased glutathione peroxidase 1 (GPx1) transcription and decreased ROS level leading to radioresistance of GSCs. MiR-153 overexpression resulted in increased ROS production and radiosensitization of GSCs. Moreover, miR-153 overexpression led to decreased neurosphere formation capacity and stem cell marker expression, and induced differentiation through ROS-mediated activation of p38 MAPK in GSCs. Nrf-2 overexpression rescued the decreased stemness and radioresistance resulting from miR-153 overexpression in GSCs. In addition, miR-153 overexpression reduced tumorigenic capacity of GSCs and increased survival in mice bearing human GSCs. These findings demonstrated that miR-153 overexpression decreased radioresistance and stemness of GSCs through targeting Nrf-2/GPx1/ROS pathway.
Highlights
A growing body of evidence suggests that a stem-like subpopulation exist in many tumor types, including glioma [1, 2]
Our results showed that nuclear factor-erythroid 2-related factor-2 (Nrf-2) was a target gene of miR-153 in glioma stem cells” (GSCs) and low level of miR-153 rescued Nrf-2 expression leading to activation of glutathione peroxidase 1 (GPx1) transcription and decreased Reactive oxygen species (ROS) level, which contributed to radioresistance of GSCs
We found that non-GSCs glioma cells displayed significantly lower basal GPx1 expression and activity than GSCs
Summary
A growing body of evidence suggests that a stem-like subpopulation exist in many tumor types, including glioma [1, 2]. These small population of cells with self-renewal capacity and immature phenotype in glioma, called “glioma stem cells” (GSCs), which exhibit stem cell properties and have ability to initiate and propagate tumors [3, 4]. Only a few molecular mechanisms for GSCs resistance to apoptotic signals have been identified. Elucidation of the molecular mechanisms underlying the therapeutic resistance of GSCs would contribute to identification of novel targets of therapeutic intervention and prolongation of patient survival
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