Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver.
OBJECTIVE
Wnt/beta-catenin activation is observed in normal liver development, regeneration, and liver cancer. Our aim was to elucidate the regulation and mechanism of this pathway in liver.


METHODS
We report the generation and characterization of liver-specific nonmutated beta-catenin-overexpressing transgenic mice. Transgenic livers were examined for their morphology and phenotype by histology, proliferation, apoptosis, and microarray analysis.


RESULTS
Transgenic livers displayed a significant increase in cytoplasmic, membranous, and nuclear beta-catenin in hepatocytes as compared with their wild-type littermates, which display a predominant membranous localization only. A 15%-20% increase in the liver weight-body weight ratio was evident in transgenic mice secondary to increased hepatocyte proliferation. Microarray analysis showed differential expression of approximately 400 genes in the transgenic livers. Epidermal growth factor receptor RNA and protein and increased levels of activated epidermal growth factor receptor and Stat3 were observed in the transgenic livers. Epidermal growth factor receptor promoter analysis showed a T-cell factor-binding site, and subsequent reporter assay confirmed epidermal growth factor receptor activation in response to Wnt-3A treatment that was abrogated by frizzled related protein 1, a known Wnt antagonist. Epidermal growth factor receptor inhibition successfully decreased liver size in transgenic mice. Next, 7 of 10 hepatoblastomas displayed simultaneous beta-catenin and epidermal growth factor receptor up-regulation, thus suggesting a strong relationship between these 2 proteins in tumors.


CONCLUSIONS
beta-Catenin transgenic mice show an in vivo hepatotrophic effect secondary to increased basal hepatocyte proliferation. Epidermal growth factor receptor seems to be a direct target of the pathway, and epidermal growth factor receptor activation might contribute toward some mitogenic effects of increased beta-catenin in liver: epidermal growth factor receptor inhibition might be useful in such states.
Tan
Xinping
X
Department of Pathology, University of Pittsburgh, School of Medicine, Pennsylvania 15261, USA.
Apte
Udayan
U
Micsenyi
Amanda
A
Kotsagrelos
Emorphia
E
Luo
Jian-Hua
JH
Ranganathan
Sarangarajan
S
Monga
Dulabh K
DK
Bell
Aaron
A
Michalopoulos
George K
GK
Monga
Satdarshan P S
SP
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D018197:Hepatoblastoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006529:Hepatomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000473:pathology / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D066246:ErbB Receptors