Wnt signaling in hepatocellular carcinoma: Analysis of mutation and expression of beta‐catenin, T‐cell factor‐4 and glycogen synthase kinase 3‐beta genes

Cui, Jian; Zhou, Xin‐Da; Liu, Yinkun; Tang, Zhao‐You; Romeih, Mahmoud

doi:10.1046/j.1440-1746.2003.02973.x

Cited by 101 publications

(91 citation statements)

References 23 publications

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“…However, mutations of β-catenin and/or APC genes are detected only in 20-30%, whereas axin1 mutations are rare in HCC [18,[33][34][35][36][37][38]. Previous reports suggest that several signaling components upstream of β-catenin may be involved for wild-type β-catenin accumulation to occur in HCC.…”

Section: Discussionmentioning

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: Discussionmentioning

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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show abstract

“…[6][7][8][9][10][11][12][13][14]34,35,39,[46][47][48][49] Dysregulation of this pathway can be caused by mutations in any components (CTNNB1, AXIN or FZD7) in colon cancers, HCCs and other cancers. 46,49,50 Suzuki et al 36,42 demonstrated recently that epigenetic loss of SFRP gene family functions may contribute to the progression of colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway

Shih

Hsieh

Lai

et al. 2007

Intl Journal of Cancer

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Oncogenic activation of the Wnt/b-catenin signaling pathway is common in hepatocellular carcinoma (HCC). The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications for carcinogenesis. Promoter hypermethylation of SFRP genes is common in human cancers. However, the role of SFRPs in HCC is not clear. Recently, we have shown that SFRP1 is frequently downregulated through promoter hypermethylation. To confirm and extend these findings, the methylation status of the other SFRP members, including SFRP2, SFRP4 and SFRP5, was examined by methylation-specific polymerase chain reaction (MS-PCR). Hypermethylation of SFRP genes, except for SFRP4, is frequent in HCCs and the levels found here were significantly higher than those seen in cirrhotic livers, chronic hepatitis livers and normal controls (p < 0.0001 for SFRP1 and SFRP2, p < 0.05 for SFRP5). To investigate the role of SFRP1 in HCCs, we used re-expression of SFRP1 in bcatenin-dependent HCC cell lines: Huh6 and HepG2. Restoration of SFRP1 attenuated Wnt signaling in those Huh6 hepatoma cells with a b-catenin gene point mutation, decreased abnormal accumulation of b-catenin in the nucleus and suppressed cell growth. Conversely, restoration of SFRP1 in HepG2 hepatoma cells with truncated bcatenin could not block the Wnt signaling pathway. Furthermore, knocking down SFRP1 by RNA interference in b-catenin-deficient cell lines (SK-Hep1) stimulated Wnt signaling and promoted cell growth. Our data suggested that SFRP1 suppressed liver cancer cells growth through Wnt canonical signaling. Moreover, b-cateninindependent noncanonical pathway might be involved in Wnt signaling activation through unknown molecules in HCC. ' 2007 Wiley-Liss, Inc.Key words: epigenetic inactivation; hepatocellular carcinoma; SFRP1; Wnt/b-catenin Hepatocellular carcinoma (HCC) is one of the most common malignant human tumors worldwide. 1-4 The major factors associated with HCC include chronic hepatitis B and C viral infections, chronic alcohol consumption, aflatoxin-B1-contaminated food and virtually all cirrhosis-inducing conditions. 4 Other etiological factors have also been proposed to lead to HCC. In addition, gender can also influence the risk and behavior of HCC, with men accounting for more cases. 5 The molecular mechanisms of hepatocarcinogenesis and the complex interactions of genetic factors remain to be elucidated.Wnt glycoproteins comprise a family of extracellular signaling ligands that play essential roles in proliferation, patterning and fate determination during normal developmental processes. [6][7][8][9][10][11][12] Although this signaling is critical for normal embryonic development, the aberrant of activation of the Wnt signal transduction pathway has been closely linked to tumorigenesis in adults. [13][14][15] b-Catenin is a crucial downstream component of the Wnt signaling pathway. When Wnt signaling is engaged, the adenomatosis polyposis coli (APC) and Axin proteins no longer bind b-catenin, with consequent b...

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“…Although these two genes are frequently up-regulated in HCC, a direct link between activation of the ␤-catenin pathway and the genes' overexpression in the liver is controversial (24)(25)(26)(27). Cyclin D1 mRNA was induced in adult Apc Ϫ/Ϫ livers on D7 and in both Apc Ϫ/Ϫ and PK͞c-Myc liver tumors (Fig.…”

Section: Liver-targeted Apc Ablation Activates ␤-Catenin Signaling Andmentioning

confidence: 99%

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

Colnot

Decaens

Niwa‐Kawakita

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

292

291

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Wnt signaling in hepatocellular carcinoma: Analysis of mutation and expression of beta‐catenin, T‐cell factor‐4 and glycogen synthase kinase 3‐beta genes

Abstract: Our present findings strongly suggest that mutations of beta-catenin, as well as overexpression of beta-catenin and the Tcf-4 gene, independently activate the Wnt pathway in HCC, with the target gene most likely to be C-myc.

Cited by 101 publications

References 23 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

SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway

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

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