β-catenin and cyclin D1 expression in human hepatocellular carcinoma

Ueta, Tsuyoshi; Ikeguchi, Masahide; Hirooka, Yasuaki; Kaibara, Nobuaki; Terada, Tadashi

doi:10.3892/or.9.6.1197

Cited by 27 publications

(22 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytoplasmic accumulation of b-catenin seen in the patients' samples may be interpreted as indicating a stage before its migration to the nucleus. Significant correlations between overexpression of cyclin D1 involved in the Wnt signaling pathway and accumulation of b-catenin in the cytoplasm have been reported by several investigators (Qiao et al, 2001;Ueta et al, 2002). In contrast to CXXC4, we observed loss of SFRP1 expression in almost all RCCs, including cases showing membranous staining of b-catenin (data not shown).…”

Section: Discussionsupporting

confidence: 75%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

View full text Add to dashboard Cite

The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

show abstract

Section: Discussionsupporting

confidence: 75%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

View full text Add to dashboard Cite

show abstract

“…We observed heterogeneous subcellular staining patterns for b-catenin in HCC (Figure 2), consistent with previous reports (Nhieu et al, 1999;Terris et al, 1999;Ueta et al, 2002). Cytoplasmic and nuclear b-catenin was observed in tumors with b-catenin mutations (Table 1, Po0.01).…”

supporting

confidence: 91%

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

et al. 2006

View full text Add to dashboard Cite

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.

show abstract

“…In addition, we show that loss of ELF results in cell-cycle deregulation, as evident by an increase in cyclin D1, Cdk4, c-Myc and MDM2 levels in elf þ /À HCC specimens. Increased expression of protein or mRNA levels of cyclin D1 and Cdks, c-Myc, and MDM2 in chronic hepatitis or HCCs has also been observed by several other groups (Ito et al, 1999;Joo et al, 2001;Sundarrajan et al, 2002;Ueta et al, 2002;Zhang et al, 2002;Masaki et al, 2003).…”

Section: Discussionmentioning

confidence: 54%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

View full text Add to dashboard Cite

Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

show abstract

β-catenin and cyclin D1 expression in human hepatocellular carcinoma

Cited by 27 publications

References 0 publications

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

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

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Contact Info

Product

Resources

About