A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs

Stem Cell Reports. 2019 Jan 8;12(1):122-134. doi: 10.1016/j.stemcr.2018.12.002.


Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC therapeutic strategies. Here, we show that miRNA-3' UTR sensor vectors can be used as a pathway-based method to identify, enrich, and analyze TICs from primary solid tumor patient samples. We have found that an miR-181ahigh subpopulation of cells sorted from primary ovarian tumor cells exhibited TIC properties in vivo, were enriched in response to continuous cisplatin treatment, and showed activation of numerous major stem cell regulatory pathways. This miRNA-sensor-based platform enabled high-throughput drug screening leading to identification of BET inhibitors as transcriptional inhibitors of miR-181a. Taken together, we provide a valuable miRNA-sensor-based approach to broaden the understanding of complex TIC regulatory mechanisms in cancers and to identify miRNA-targeting drugs.

Keywords: BET inhibitors; miR-181a; miRNA sensor; ovarian cancer; tumor heterogeneity; tumor-initiating cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • Antineoplastic Agents / pharmacology*
  • Biosensing Techniques / methods*
  • Cell Line, Tumor
  • Drug Discovery / methods*
  • Female
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology


  • 3' Untranslated Regions
  • Antineoplastic Agents
  • MicroRNAs