Hepatocellular carcinoma development induced by conditional beta-catenin activation in Lkb1+/- mice.
The development of hepatocellular carcinomas (HCC) appears to be a multistep process that takes several decades in humans. However, the identities of specific gene alterations and their contribution to HCC pathogenesis remain poorly understood. We previously reported that Lkb1(+/-) mice spontaneously develop multiple hepatic nodular foci (NdFc) followed by HCC, and that the conditional activation of beta-catenin in Catnb(lox(ex3)) mouse livers alone does not cause tumor formation. We show here that the conditional activation of beta-catenin accelerates HCC development in Catnb(+/lox(ex3))Lkb1(+/-) compound mutant mice, affecting displastic hepatocytes in NdFc that suffered LOH at the Lkb1 locus. We further show that beta-catnin activation provides HCC with a growth advantage as well as transplantability. These results suggest that the loss of Lkb1 contributes to the formation of dysplastic NdFc, and that Wnt signaling activation is involved in ensuing progression toward HCC. A combination of these sequential changes can be a practical model for a subset of human HCC.
Miyoshi
Hiroyuki
H
Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Deguchi
Atsuko
A
Nakau
Masayuki
M
Kojima
Yasushi
Y
Mori
Akira
A
Oshima
Masanobu
M
Aoki
Masahiro
M
Taketo
Makoto Mark
MM
D055372:AMP-Activated Protein Kinases; D000818:Animals; D019927:Cyclin E / Q000032:analysis; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
C495267:CTNNB1 protein, mouse; D019927:Cyclin E; D051153:Wnt Proteins; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases