Activation of Wnt/beta-catenin pathway during hepatocyte growth factor-induced hepatomegaly in mice.
Hepatocyte growth factor (HGF) and beta-catenin both play a crucial role in stimulating hepatocyte proliferation, but whether these 2 pathways cooperate in inducing hepatocyte proliferation is unclear. We have previously reported that beta-catenin forms a complex with c-Met (HGF receptor) that undergoes dissociation because of beta-catenin tyrosine phosphorylation on stimulation by HGF. It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice. In addition, recently characterized beta-catenin transgenic mice also showed hepatomegaly. The present study was based on the hypothesis that HGF-induced hepatomegaly is mediated, at least in part, by activation of the Wnt/beta-catenin pathway. Here we report that delivery of the human HGF gene delivery in mice led to hepatomegaly via beta-catenin activation in the liver in 1- and 4-week studies. The mechanisms of beta-catenin activation in the 1-week study included loss of c-Met-beta-catenin association as well as canonical beta-catenin activation, leading to its nuclear translocation. In the 4-week study, beta-catenin activation was observed via canonical mechanisms, whereas the c-Met-beta-catenin complex remained unchanged. In both studies there was an associated increase in the E-cadherin-beta-catenin association at the membrane. In addition, we generated liver-specific beta-catenin knockout mice, which demonstrated significantly smaller livers. HGF gene delivery failed to induce hepatomegaly in these beta-catenin conditionally null mice. In conclusion, beta-catenin- and HGF-mediated signaling pathways cooperate in hepatocyte proliferation, which may be crucial in liver development, regeneration following partial hepatectomy, and pathogenesis of hepatocellular carcinoma.
Apte
Udayan
U
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15216, USA.
Zeng
Gang
G
Muller
Peggy
P
Tan
Xinping
X
Micsenyi
Amanda
A
Cieply
Benjamin
B
Dai
Chunsun
C
Liu
Youhua
Y
Kaestner
Klaus H
KH
Monga
Satdarshan P S
SP
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006529:Hepatomegaly / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010957:Plasmids; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D051153:Wnt Proteins; D051176:beta Catenin; D017228:Hepatocyte Growth Factor