Liver-targeted disruption of<i>Apc</i>in mice activates β-catenin signaling and leads to hepatocellular carcinomas

Colnot, Sabine; Decaens, Thomas; Niwa‐Kawakita, Michiko; Godard, Cécile; Hamard, Ghislaine; Kahn, Axel; Giovannini, Marco; Perret, Christine

doi:10.1073/pnas.0404761101

Cited by 292 publications

(320 citation statements)

References 36 publications

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“…In addition, the protein levels of c-Myc and cyclin D1 were determined which are known as downstream target genes of TCF/β-catenin activation. Although these genes are commonly upregulated in HCC, a direct link between activation of β-catenin and induction of c-Myc and/ or cyclin D1 in the liver is controversial [28][29][30][31]. In FOCUS-Wnt3 cells, overexpression of Wnt3 induced both cyclin D1 and c-Myc expression (Fig.…”

Section: Overexpression Of Wnt3 Activates the Wnt/β-catenin Pathway Imentioning

confidence: 99%

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Kim¹,

Lee²,

Tsedensodnom³

et al. 2008

Journal of Hepatology

171

173

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Background/Aims-The canonical Wnt signaling is frequently activated in human hepatocellular carcinoma (HCC). We previously demonstrated that up-regulation of Frizzled-7 receptor (FZD7) in HCC was associated with nuclear accumulation of wild-type β-catenin. Here, we investigated Wnt ligand(s) that may activate the Wnt/β-catenin pathway through FZD7 in HCC cells. Results-In hepatitis B virus (HBV)-induced HCC, Wnt3 was upregulated in tumor and peritumoral tissues compared to normal liver and downstream β-catenin target genes were also increased in these samples. Activation of the Wnt/β-catenin pathway in FOCUS-Wnt3 cells was demonstrated by β-catenin accumulation, enhanced TCF transcriptional activity and proliferation rate. The activation of Wnt/β-catenin signaling in FOCUS-Wnt3 was abolished by a knockdown of FZD7 expression by siRNA. More important, a specific Wnt3-FZD7 interaction was observed by co-immunoprecipitation experiments, which suggest that the action of Wnt3 was mediated via FZD7. Methods-To identifyConclusions-These findings demonstrate a functional interaction between Wnt3 and FZD7 leading to activation of the Wnt/β-catenin signaling pathway in HCC cells and may play a role during hepatocarcinogenesis.

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Section: Overexpression Of Wnt3 Activates the Wnt/β-catenin Pathway Imentioning

confidence: 99%

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Kim¹,

Lee²,

Tsedensodnom³

et al. 2008

Journal of Hepatology

171

173

View full text Add to dashboard Cite

show abstract

“…We demonstrated that among the various liver b-catenin target genes tested (Cadoret et al, 2002;Yamamoto et al, 2003;Colnot et al, 2004;Ovejero et al, 2004), three were good markers of active b-catenin signaling: GS, GPR49 and GLT-1. Immunohistochemical analyses showed that GS is a marker of b-catenin activation in human HCC.…”

mentioning

confidence: 93%

Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas

et al. 2006

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Perturbations to the Wnt signaling pathway have been implicated in a large proportion of human hepatocellular carcinomas (HCCs). Activating b-catenin mutations and loss of function mutations in Axin1 are thought to be functionally equivalent. We examined the Wnt pathway in HCC by comparing the expression of b-catenin target genes and the level of b-catenin-dependent transcriptional activation, in 45 HCC tumors and four cell lines. Among these samples, b-catenin and AXIN1 were mutated in 20 and seven cases, respectively. We found a significant correlation between activated b-catenin mutations and overexpression of mRNA for the target genes glutamine synthetase (GS), G-protein-coupled receptor (GPR)49 and glutamate transporter (GLT)-1 (P ¼ 0.0001), but not for the genes ornithine aminotransferase, LECT2, c-myc and cyclin D1. We also showed that GS is a good immunohistochemical marker of b-catenin activation in HCC. However, we observed no induction of GS, GPR49 or GLT-1 in the five inactivated Axin1 tumors. b-Catenin-dependent transcriptional activation in two Axin1-mutated HCC cell lines was much weaker than in b-catenin-mutated cell lines. Our results strongly suggest that in HCC, contrary to expectation, the loss of function of Axin1 is not equivalent to the gain of function of b-catenin. Our results also suggest that the tumor suppressor function of Axin1 in HCC may be related to another, non-Wnt pathway.

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“…Slides were incubated with diluted primary antibodies overnight at 4°C. The following primary antibodies were used: mouse anti-␤-catenin (1:500 dilution) (Becton and Dickinson, Franklin Lakes, NJ) 16,17 ; mouse anti-GS (1: 500 dilution, Becton and Dickinson) 16,17 ; rabbit anti-GLT-1 (1:500 dilution) (gift from Masahiko Watanabe) 21,22 ; sheep anti-CYP1A2 (1:1,000 dilution) (Chemicon, Temecula, CA) 23 ; rabbit anti-CYP2E1 (1: 1,000 dilution) (gift from Magnus Ingelman-Sundberg). 16,24 Biotinylated anti-rabbit (Vector Laboratories) and anti-sheep (Jackson Immunoresearch, West Grove, PA) antibodies were used as secondary antibodies at a 1:200 dilution.…”

Section: Methodsmentioning

confidence: 99%

Liver-specific loss of β-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice

et al. 2006

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There is accumulating evidence that Wnt/␤-catenin signaling is involved in the regulation of liver development and physiology. The presence of genetic alterations resulting in constitutive ␤-catenin stabilization in human and murine liver tumors also implicates this pathway in hepatocyte proliferation. In the present study, we generated hepatocyte-specific ␤-catenin knockout mice to explore the role of ␤-catenin in liver function. Conditional knockout mice were born at the expected Mendelian ratio and developed normally to adulthood, indicating ␤-catenin is dispensable for essential liver function under normal breeding conditions. However, the liver mass of knockout mice was 20% less than those of mice in the control groups. Expression analysis revealed loss of genes required for glutamine synthesis in knockout mice. Loss of the liver glutamine synthesis pathway did not affect the blood ammonia level in mice fed a standard diet, yet, knockout mice showed significantly elevated blood ammonia levels with high-protein dietary feeding. Furthermore, the expression of two cytochrome P450 enzymes, CYP1A2 and CYP2E1, was almost completely abolished in livers from hepatocyte-specific ␤-catenin knockout mice. Consequently, these mice were resistant to acetaminophen challenge, confirming the requirement of these cytochrome P450 enzymes for metabolism of xenobiotic substances. ␤ -Catenin is an adapter protein that fulfills two distinct roles in cells. As a part of an adherens junction complex, it interacts with transmembrane proteins of the cadherin family to promote cell-cell adhesion. In addition, ␤-catenin is an integral part of the canonical Wnt signaling pathway known to regulate cell proliferation, differentiation, and stem cell maintenance in a wide variety of tissues. 1-3 Wnt ligands are secreted proteins that bind to cognate frizzled receptors expressed in the cell membrane of Wnt-responsive cells. In the absence of Wnt signals, cytoplasmic ␤-catenin is phosphorylated by glycogen synthase kinase 3␤, a modification that triggers rapid proteosomal degradation of ␤-catenin. Upon stimulation with Wnt ligands, cytoplasmic ␤-catenin is stabilized and translocates to the nucleus, where it forms active transcription complexes with members of the TCF/LEF1 transcription factor family.There is accumulating evidence that indicates a role for Wnt/␤-catenin signaling in hepatocyte proliferation. Micsenyi et al. reported nuclear/cytoplasmic localization of ␤-catenin in hepatocytes during early developmental stages, which gradually decrease with progression of organ development. During liver development, the level of nuclear/cytoplasmic ␤-catenin expression correlates well with the proliferative activity of hepatocytes. 4 Suppression of ␤-catenin by antisense oligonucleotides in ex vivo liver cultures results in decreased cell proliferation and increased apoptosis of hepatocytes. 5 Conversely, transgenic expression of N-terminally truncated ␤-catenin results in increased hepatocyte proliferation and hepatomegaly, 6 a finding that ...

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Liver-targeted disruption ofApcin mice activates β-catenin signaling and leads to hepatocellular carcinomas

Cited by 292 publications

References 36 publications

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas

Liver-specific loss of β-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice

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