Mice with Hepatic Loss of the Desmosomal Protein γ-Catenin Are Prone to Cholestatic Injury and Chemical Carcinogenesis.
γ-Catenin, an important component of desmosomes, may also participate in Wnt signaling. Herein, we dissect the role of γ-catenin in liver by generating conditional γ-catenin knockout (KO) mice and assessing their phenotype after bile duct ligation (BDL) and diethylnitrosamine-induced chemical carcinogenesis. At baseline, KO and wild-type littermates showed comparable serum biochemistry, liver histology, and global gene expression. β-Catenin protein was modestly increased without any change in Wnt signaling. Desmosomes were maintained in KO, and despite no noticeable changes in gene expression, differential detergent fractionation revealed quantitative and qualitative changes in desmosomal cadherins, plaque proteins, and β-catenin. Enhanced association of β-catenin to desmoglein-2 and plakophilin-3 was observed in KO. When subjected to BDL, wild-type littermates showed specific changes in desmosomal protein expression. In KO, BDL deteriorated baseline compensatory changes, which manifested as enhanced injury and fibrosis. KO also showed enhanced tumorigenesis to diethylnitrosamine treatment because of Wnt activation, as also verified in vitro. γ-Catenin overexpression in hepatoma cells increased its binding to T-cell factor 4 at the expense of β-catenin-T-cell factor 4 association, induced unique target genes, affected Wnt targets, and reduced cell proliferation and viability. Thus, γ-catenin loss in liver is basally well tolerated. However, after insults like BDL, these compensations at desmosomes fail, and KO show enhanced injury. Also, γ-catenin negatively regulates tumor growth by affecting Wnt signaling.
Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China; Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Lili
L
Zhou
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Tirthadipa
T
Pradhan-Sundd
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Minakshi
M
Poddar
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Sucha
S
Singh
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Alex
A
Kikuchi
Department of Cell Biology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Donna B
DB
Stolz
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
Weinian
W
Shou
Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
Zongfang
Z
Li
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Kari N
KN
Nejak-Bowen
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania; Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania. Electronic address: smonga@pitt.edu.
Satdarshan P
SP
Monga
D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D003896:Desmosomes / Q000378:metabolism*; D004052:Diethylnitrosamine; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000502:physiology; D051185:gamma Catenin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C495267:CTNNB1 protein, mouse; C495293:Jup protein, mouse; D009363:Neoplasm Proteins; D051176:beta Catenin; D051185:gamma Catenin; D004052:Diethylnitrosamine