title: MiR-181b sensitizes glioma cells to teniposide by targeting MDM2.
abstract: 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.
authors.forename: Yan-chang
authors.initials: YC
authors.lastname: Sun
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Cheng-cheng
authors.initials: CC
authors.lastname: Guo
authors.forename: Ke
authors.initials: K
authors.lastname: Sai
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Fu-rong
authors.initials: FR
authors.lastname: Chen
authors.forename: Qun-ying
authors.initials: QY
authors.lastname: Yang
authors.forename: Yin-sheng
authors.initials: YS
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Tony Shing-shun
authors.initials: TS
authors.lastname: To
authors.forename: Zong-ping
authors.initials: ZP
authors.lastname: Zhang
authors.forename: Yong-gao
authors.initials: YG
authors.lastname: Mu
authors.affiliation: Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China. chenzhp@sysucc.org.cn.
authors.forename: Zhong-ping
authors.initials: ZP
authors.lastname: Chen
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013713:Teniposide / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D013713:Teniposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2