REV3L confers chemoresistance to cisplatin in human gliomas: The potential of its RNAi for synergistic therapy

¹ Department of Neurological Surgery, Brain Tumor Research Center, First Clinical Medical School, Harbin Medical University, Harbin, China; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
² State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
³ State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁴ Department of Neurological Surgery, Brain Tumor Research Center, First Clinical Medical School, Harbin Medical University, Harbin, China
⁵ Department of Neurological Surgery, Shanghai 6th People Hospital, Shanghai Jiao Tong University, Shanghai, China

^* To whom correspondence should be addressed. E-mail: guangsz{at}hotmail.com.

	Abstract

The REV3L gene, encoding the catalytic subunit of human polymerase , plays a significant role in the cytotoxicity, mutagenicity and chemoresistance of certain tumors. However, the role of REV3L in regulating the sensitivity of glioma cells to chemotherapy remains unknown. In this study, we investigated the expression of REV3L gene in 10 normal brain specimens and 30 human glioma specimens, and examined the value of REV3L as a potential modulator of cellular response to various DNA damaging agents. RT-PCR/Real-Time PCR analysis revealed that REV3L was overexpressed in human gliomas compared with normal brain tissues. Glioma cell model with stable overexpression of REV3L was set up and used to probe the role of REV3L in cisplatin treatment, upregulation of REV3L markedly attenuated cisplatin-induced apoptosis of mitochondrial apoptotic pathway. We, therefore, assessed the REV3L-targeted treatment modality that combines suppression of REV3L expression using RNA interference (RNAi) with the cytotoxic effects of DNA damaging agents. We found that down-regulation of REV3L expression significantly enhanced the sensitivity of glioma cells to cisplatin, which was evidenced by the increased apoptosis rate as well as marked alterations in Bcl-2, Bcl-xl and Bax expression levels, and meanwhile reduced mutation frequencies in surviving glioma cells. These results suggest that REV3L may potentially contribute to gliomagenesis and play a crucial role in regulating cellular response to DNA cross-linking agent cisplatin. Our findings provide a novel strategy that RNAi targeting REV3L combined with chemotherapy has synergistic therapeutic effects on glioma cells, which warrants further investigation as an effective therapeutic regimen for patients with this malignancy.

Key Words: chemoresistance, cisplatin, glioma, REV3L, RNAi

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