Morpholino oligonucleotide-triggered beta-catenin knockdown compromises normal liver regeneration.
OBJECTIVE
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.
Sodhi
Dimple
D
Department of Pathology, School of Medicine, University of Pittsburgh, S421-BST, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
Micsenyi
Amanda
A
Bowen
William C
WC
Monga
Dulabh K
DK
Talavera
Juan-Carlos Lopez
JC
Monga
Satdarshan P S
SP
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D060172:Morpholinos; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D055293:Receptors, Urokinase Plasminogen Activator; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; C524900:Plaur protein, rat; D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019938:Cyclin D1