Morpholino oligonucleotide-triggered beta-catenin knockdown compromises normal liver regeneration

J Hepatol. 2005 Jul;43(1):132-41. doi: 10.1016/j.jhep.2005.02.019. Epub 2005 Apr 25.

Abstract

Background/aims: Wnt/beta-catenin activation is seen during early liver regeneration (LR) observed as stabilization and translocation to the nucleus followed by an overall decrease. However, beta-catenin continues to be in hepatocyte nucleus and membrane, secondary to its increased gene expression at 6-72 h.

Methods: In the present study, we examined the effect of ablating beta-catenin transcription on LR. Twelve male fisher rats were subjected to two-third partial hepatectomy followed by administration of beta-catenin antisense phospho-morpholino oligonucleotide (AS) in six or mismatch control (CON) injection in the remaining 6 via superior mesenteric vein. Three animals from each group were sacrificed at 24 h and 7 days for liver assessment.

Results: AS group exhibited a significant decrease in total beta-catenin at 24 h. A significant decrease in liver/body weight ratio was also observed in the AS group at 24 h and 7 days that was due to decreased proliferation. Among the targets of this pathway c-myc and uPAR levels showed significant decrease while cyclin-D1 remained unaffected.

Conclusions: We demonstrate the importance of beta-catenin in early liver regeneration especially in hepatocyte proliferation. Also, c-myc and uPAR might be crucial downstream effectors of beta-catenin during liver regeneration.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclin D1 / metabolism
  • Hepatectomy / methods
  • Hepatocytes / cytology
  • Liver / cytology
  • Liver / metabolism
  • Liver / physiology
  • Liver Regeneration / drug effects*
  • Male
  • Morpholines / pharmacology*
  • Morpholinos
  • Oligonucleotides, Antisense / pharmacology
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Rats
  • Rats, Inbred F344
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Urokinase Plasminogen Activator
  • Time Factors
  • Transcription, Genetic / drug effects*

Substances

  • Morpholines
  • Morpholinos
  • Oligonucleotides, Antisense
  • Plaur protein, rat
  • Proto-Oncogene Proteins c-myc
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Cyclin D1