Short loop-targeting oligoribonucleotides antagonize Lin28 and enable pre-let-7 processing and suppression of cell growth in let-7-deficient cancer cells

Nucleic Acids Res. 2015 Jan;43(2):e9. doi: 10.1093/nar/gku1090. Epub 2014 Nov 6.


MicroRNAs (miRNAs) originate from stem-loop-containing precursors (pre-miRNAs, pri-miRNAs) and mature by means of the Drosha and Dicer endonucleases and their associated factors. The let-7 miRNAs have prominent roles in developmental differentiation and in regulating cell proliferation. In cancer, the tumor suppressor function of let-7 is abrogated by overexpression of Lin28, one of several RNA-binding proteins that regulate let-7 biogenesis by interacting with conserved motifs in let-7 precursors close to the Dicer cleavage site. Using in vitro assays, we have identified a binding site for short modified oligoribonucleotides ('looptomirs') overlapping that of Lin28 in pre-let-7a-2. These looptomirs selectively antagonize the docking of Lin28, but still permit processing of pre-let-7a-2 by Dicer. Looptomirs restored synthesis of mature let-7 and inhibited growth and clonogenic potential in Lin28 overexpressing hepatocarcinoma cells, thereby demonstrating a promising new means to rescue defective miRNA biogenesis in Lin28-dependent cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation
  • HEK293 Cells
  • Humans
  • MicroRNAs / chemistry
  • MicroRNAs / metabolism*
  • Neoplasms / enzymology
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Oligoribonucleotides / chemistry
  • Oligoribonucleotides / metabolism*
  • RNA Precursors / chemistry
  • RNA Precursors / metabolism
  • RNA Processing, Post-Transcriptional*
  • RNA-Binding Proteins / antagonists & inhibitors*
  • RNA-Binding Proteins / metabolism
  • Ribonuclease III / metabolism


  • LIN28B protein, human
  • MicroRNAs
  • Oligoribonucleotides
  • RNA Precursors
  • RNA-Binding Proteins
  • mirnlet7 microRNA, human
  • Ribonuclease III