Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer

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In Vitro Selection of Engineered Transcriptional Repressors for Targeted Epigenetic Silencing

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Tetsuya Shindo1,2, Takeshi Niinuma2, Naotaka Nishiyama1

  • 1Department of Urology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Oncotarget
|June 1, 2018
PubMed

Insights

Downregulation of miR-200b contributes to cisplatin resistance in bladder cancer (BCa). Restoring miR-200b expression via demethylation can re-sensitize BCa cells to cisplatin, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Cisplatin (CDDP) is a cornerstone chemotherapy for bladder cancer (BCa).
  • Acquired resistance to CDDP significantly limits treatment efficacy in BCa.
  • Understanding the molecular mechanisms underlying CDDP resistance is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To identify microRNAs (miRNAs) implicated in CDDP resistance in BCa.
  • To investigate the role of miR-200 family members in CDDP resistance.
  • To explore the therapeutic potential of targeting miR-200b epigenetic silencing.

Main Methods:

  • Establishment of CDDP-resistant BCa cell lines (T24RC and EJ138RC).
  • TaqMan and microarray analyses to profile miRNA and gene expression.
  • Assessment of DNA methylation status and its correlation with miRNA expression.
  • Pharmacological demethylation using 5-aza-2'-deoxycytidine.

Main Results:

  • Members of the miR-200 family, particularly miR-200b, were significantly downregulated in CDDP-resistant BCa cells.
  • Downregulation of miR-200b was linked to CpG island hypermethylation.
  • Demethylation therapy restored miR-200b expression and enhanced sensitivity to CDDP.
  • Combined treatment with 5-aza-2'-deoxycytidine and CDDP inhibited proliferation of resistant cells.
  • miR-200b re-expression modulated genes associated with CDDP sensitivity (e.g., IGFBP3, ICAM1, TNFSF10).
  • Inverse association between miR-200b expression and methylation was observed in primary BCa, with low expression/high methylation correlating with poor survival.

Conclusions:

  • Epigenetic silencing of miR-200b is a key mechanism contributing to CDDP resistance in BCa.
  • miR-200b downregulation serves as a potential biomarker for CDDP resistance.
  • Targeting miR-200b epigenetic silencing represents a promising therapeutic avenue for overcoming CDDP resistance in BCa.
Keywords:
DNA methylationbladder cancercisplatin resistancehistone modificationmiRNA

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