Differential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis

Nat Commun. 2016 Mar 18;7:11012. doi: 10.1038/ncomms11012.

Abstract

Downregulation of a predominantly hepatocyte-specific miR-122 is associated with human liver cancer metastasis, whereas miR-122-deficient mice display normal liver function. Here we show a functional conservation of miR-122 in the TGFβ pathway: miR-122 target site is present in the mouse but not human TGFβR1, whereas a noncanonical target site is present in the TGFβ1 5'UTR in humans and other primates. Experimental switch of the miR-122 target between the receptor TGFβR1 and the ligand TGFβ1 changes the metastatic properties of mouse and human liver cancer cells. High expression of TGFβ1 in human primary liver tumours is associated with poor survival. We identify over 50 other miRNAs orthogonally targeting ligand/receptor pairs in humans and mice, suggesting that these are evolutionarily common events. These results reveal an evolutionary mechanism for miRNA-mediated gene regulation underlying species-specific physiological or pathological phenotype and provide a potentially valuable strategy for treating liver-associated diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Allografts
  • Animals
  • Base Pairing / genetics
  • Base Sequence
  • Cell Line
  • Conserved Sequence / genetics
  • Evolution, Molecular
  • Genome
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / secondary*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction* / genetics
  • Species Specificity
  • Transforming Growth Factor beta / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • 5' Untranslated Regions
  • MIRN122 microRNA, human
  • MicroRNAs
  • Mirn122 microRNA, mouse
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I