MiR-181b sensitizes glioma cells to teniposide by targeting MDM2

BMC Cancer

Yan-chang Sun²  Jing Wang¹  Cheng-cheng Guo⁴  Ke Sai⁴  Jian Wang⁴  Fu-rong Chen⁴  Qun-ying Yang⁴  Yin-sheng Chen⁴  Jie Wang⁴  Tony Shing-shun To¹  Zong-ping Zhang³  Yong-gao Mu⁴  Zhong-ping Chen⁴ 

[1] Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong

[2] Current address: Department of Neurosurgery, Hainan Provincial Nongken Hospital, 48 Bashuitang Road, Longhua Distric, Haikou, Hainan 570311, China

[3] Department of Neurosurgery, Guangdong Medical College, Zhanjiang, Guangdong, China

[4] Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China

关键词: Mouse double minute 2 homolog (MDM2);    Glioma;    Teniposide;    miR-181b;   

Others  :  1134779
DOI  :  10.1186/1471-2407-14-611

 received in 2014-02-18, accepted in 2014-08-21,  发布年份 2014

【 摘 要 】

Background

Although the incidence of glioma is relatively low, it is the most malignant tumor of the central nervous system. The prognosis of high-grade glioma patient is very poor due to the difficulties in complete resection and resistance to radio-/chemotherapy. Therefore, it is worth investigating the molecular mechanisms involved in glioma drug resistance. MicroRNAs have been found to play important roles in tumor progression and drug resistance. Our previous work showed that miR-181b is involved in the regulation of temozolomide resistance. In the current study, we investigated whether miR-181b also plays a role in antagonizing the effect of teniposide.

Methods

MiR-181b expression was measured in 90 glioma patient tissues and its relationship to prognosis of these patients was analyzed. Cell sensitivity to teniposide was tested in 48 primary cultured glioma samples. Then miR-181b stably overexpressed U87 cells were generated. The candidate genes of miR-181b from our previous study were reanalyzed, and the interaction between miR-181b and target gene MDM2 was confirmed by dual luciferase assay. Cell sensitivity to teniposide was detected on miR-181b over expressed and MDM2 down regulated cells.

Results

Our data confirmed the low expression levels of miR-181b in high-grade glioma tissues, which is related to teniposide resistance in primary cultured glioma cells. Overexpression of miR-181b increased glioma cell sensitivity to teniposide. Through target gene prediction, we found that MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3’-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b.

Conclusions

MiR-181b is an important positive regulator on glioma cell sensitivity to teniposide. It confers glioma cell sensitivity to teniposide through binding to the 3’-UTR region of MDM2 leading to its reduced expression. Our findings not only reveal the novel mechanism involved in teniposide resistance, but also shed light on the optimization of glioma treatment in the future.

【 授权许可】

   
2014 Sun et al.; licensee BioMed Central Ltd.

【 图 表 】

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