Evidence for a role of E-cadherin in suppressing liver carcinogenesis in mice and men.
The cell adhesion molecule E-cadherin has critical functions in development and carcinogenesis. Impaired expression of E-cadherin has been associated with disrupted tissue homeostasis, progression of cancer and a worse patient prognosis. So far, the role of E-cadherin in homeostasis and carcinogenesis of the liver is not well understood. By use of a mouse model with liver-specific deletion of E-cadherin and administration of the carcinogen diethylnitrosamine, we demonstrate that loss of E-cadherin expression in hepatocytes results in acceleration of the growth of hepatocellular carcinoma (HCC). In contrast, liver regeneration is not disturbed in mice lacking E-cadherin expression in hepatocytes. In human HCC, we observed four different expression patterns of E-cadherin. Notably, atypical cytosolic expression of E-cadherin was positively correlated with a poorer patient prognosis. The median overall survival of patients with HCC expressing E-cadherin on the membrane only was 221 weeks (95% confidence interval: 51-391) compared with 131 weeks in patients with cytosolic expression (95% confidence interval: 71-191 weeks; P < 0.05). In conclusion, we demonstrate that impaired expression of E-cadherin promotes hepatocellular carcinogenesis and is associated with a worse prognosis in humans.
Institute for Biotechnology and Molecular Animal Breeding, The Gene Center.
Marlon R
MR
Schneider
Institute for Biotechnology and Molecular Animal Breeding, The Gene Center, Department of Internal Medicine II and.
Felix
F
Hiltwein
Institute for Biotechnology and Molecular Animal Breeding, The Gene Center, Department of Internal Medicine II and.
Jessica
J
Grill
Laboratory for Functional Genome Analysis, The Gene Center, University of Munich, 81377 Munich, Germany.
Helmut
H
Blum
Laboratory for Functional Genome Analysis, The Gene Center, University of Munich, 81377 Munich, Germany.
Stefan
S
Krebs
Laboratory for Functional Genome Analysis, The Gene Center, University of Munich, 81377 Munich, Germany.
Andrea
A
Klanner
Laboratory for Functional Genome Analysis, The Gene Center, University of Munich, 81377 Munich, Germany.
Stefan
S
Bauersachs
Department of Surgery, University of Magdeburg, Magdeburg, Germany.
Christiane
C
Bruns
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Thomas
T
Longerich
Institute of Pathology, University of Munich, 80337 Munich, Germany and.
David
D
Horst
Institute of Pathology, University of Munich, 80337 Munich, Germany and.
Lydia
L
Brandl
Department of Internal Medicine II and.
Enrico
E
de Toni
Department of Internal Medicine II and.
Andreas
A
Herbst
Department of Internal Medicine II and German Cancer Consortium (DKTK) and the German Cancer Research Center, Heidelberg, Germany fkolligs@med.uni-muenchen.de.
Frank T
FT
Kolligs
D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D064200:Cdh1 Proteins / Q000502:physiology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D012333:RNA, Messenger