CCAR1 5' UTR as a natural miRancer of miR-1254 overrides tamoxifen resistance

Cell Res. 2016 Jun;26(6):655-73. doi: 10.1038/cr.2016.32. Epub 2016 Mar 22.

Abstract

MicroRNAs (miRNAs) typically bind to unstructured miRNA-binding sites in target RNAs, leading to a mutual repression of expression. Here, we report that miR-1254 interacts with structured elements in cell cycle and apoptosis regulator 1 (CCAR1) 5' untranslated region (UTR) and this interaction enhances the stability of both molecules. miR-1254 can also act as a repressor when binding to unstructured sites in its targets. Interestingly, structured miR-1254-targeting sites act as both a functional RNA motif-sensing unit, and an independent RNA functional unit that enhances miR-1254 expression. Artificially designed miRNA enhancers, termed "miRancers", can stabilize and enhance the activity of miRNAs of interest. We further demonstrate that CCAR1 5' UTR as a natural miRancer of endogenous miR-1254 re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen. Thus, our study presents a novel model of miRNA function, wherein highly structured miRancer-like motif-containing RNA fragments or miRancer molecules specifically interact with miRNAs, leading to reciprocal stabilization.

MeSH terms

  • 3' Untranslated Regions / genetics
  • 5' Untranslated Regions / genetics*
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism
  • Base Sequence
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Models, Biological
  • RNA Stability / drug effects
  • RNA Stability / genetics
  • Tamoxifen / pharmacology*
  • Tamoxifen / therapeutic use

Substances

  • 3' Untranslated Regions
  • 5' Untranslated Regions
  • AGO2 protein, human
  • Apoptosis Regulatory Proteins
  • Argonaute Proteins
  • CCAR1 protein, human
  • Cell Cycle Proteins
  • MIRN1254 microRNA, human
  • MicroRNAs
  • Tamoxifen