MicroRNA-203 Is a Prognostic Indicator in Bladder Cancer and Enhances Chemosensitivity to Cisplatin via Apoptosis by Targeting Bcl-w and Survivin

PLoS One. 2015 Nov 23;10(11):e0143441. doi: 10.1371/journal.pone.0143441. eCollection 2015.

Abstract

Resistance to cisplatin-based chemotherapy is a major cause of treatment failure in advanced bladder cancer (BC) patients. There is increasing evidence that microRNAs are involved in the development and progression of BC. However, little is known about the function of microRNAs in predicting the effect of adjuvant chemotherapy on BC survival and regulating response to cisplatin. To address this issue, we employed RT-qPCR to evaluate the clinical significance of miR-203 expression in 108 tissues of BC patients receiving cisplatin-based adjuvant chemotherapy, and performed in vitro studies to explore chemotherapeutic sensitivity to cisplatin in miR-203 overexpressing BC cells. We found miR-203 levels were significantly lower in BC progression group than non-progression group (P<0.001). ROC curve analysis illustrated miR-203 could significantly distinguish progressed patients from those without progression (P<0.001), yielding an area under the ROC curve of 0.839 (95% CI, 0.756-0.903). Moreover, low miR-203 expression correlated with shortened progression free survival (PFS) and overall survival (OS) of BC patients, and was an independent prognostic factor. Overexpression of miR-203 in 5637 and T24 BC cells could decrease cell viability, enhance cisplatin cytotoxicity, and promote apoptosis. Western blotting and luciferase reporter assay showed Bcl-w and Survivin were direct downstream targets of miR-203. There was also a significant inverse association between miR-203 and Bcl-w or Survivin expression in BC tissues (r = -0.781, -0.740, both P<0.001). In conclusion, decreased miR-203 predicts progression and poor prognosis for BC patients treated with cisplatin-based chemotherapy while miR-203 overexpression can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism*
  • Base Sequence
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use*
  • Disease Progression
  • Disease-Free Survival
  • Female
  • HEK293 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Molecular Sequence Data
  • Multivariate Analysis
  • Prognosis
  • Proportional Hazards Models
  • Survivin
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L2 protein, human
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • MIRN203 microRNA, human
  • MicroRNAs
  • Survivin
  • Cisplatin

Grant support

This work was supported by National Natural Science Foundation of China (http://www.nsfc.gov.cn/) to CW (No. 81271916); National Natural Science Foundation of China (http://www.nsfc.gov.cn/) to XZ (No. 81301506); Natural Science Foundation of Shandong Province (http://www.sdnsf.gov.cn/portal/) to XZ (ZR2013HQ063); and Doctoral Program of Higher Education of China (http://www.cutech.edu.cn/cn/kyjj/gdxxbsdkyjj/A010301index_1.htm) to XZ (No. 20130131120067).