WNT Signaling Pathway and Stem Cell Signaling Network

Katoh, Masuko; Katoh, Masaru

doi:10.1158/1078-0432.ccr-06-2316

Cited by 704 publications

(618 citation statements)

References 40 publications

(30 reference statements)

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“…In a physiological context, b-catenin and DNp63 regulate proliferation or differentiation of epidermal and mammary progenitor/stem cells (Senoo et al, 2007;Ambler and Maatta, 2009;Pece et al, 2010). In tumours, they have been implicated in the maintenance of the stemness of cancer stem cells (Katoh and Katoh, 2007;Zucchi et al, 2008). These observations suggest that the cross-talk between DNp63 and b-catenin may represent a major regulator checkpoint in the initiation, progression and dissemination of tumours of epithelial origin.…”

Section: Discussionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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The DNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. DNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominantnegative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of DNp63 overexpression is not fully understood. Here, we show that the expression of DNp63 is regulated by the Wnt/b-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that DNp63 and b-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the b-catenin pathway may contribute to overexpression of DNp63 during tumour progression, in a cell type-specific manner.

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Section: Discussionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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“…In this respect it should be noted that we could not investigate large b-catenin gene deletions, which are known to occur in hepatoblastoma. 5,27,28 Furthermore, we cannot exclude alterations in Wnt regulators acting upstream of b-catenin, 29 such as AXIN1 and AXIN2, implicated in hepatoblastoma cases negative for mutations in the b-catenin gene but positive for b-catenin protein accumulation. 28,30 With regard to correlations with histology, it is noteworthy that b-catenin immunostaining tended to be more evident in embryonal and in mesenchymal areas in epithelial and in mixed epithelial/ mesenchymal hepatoblastoma, respectively.…”

Section: Discussionmentioning

confidence: 99%

Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

et al. 2008

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Hepatoblastoma, a rare embryonic tumor that may arise sporadically or in the context of hereditary syndromes (familial adenomatous polyposis and Beckwith-Wiedemann's) is the most frequent liver cancer of childhood. Deregulation of the APC/b-catenin pathway occurs in a consistent fraction of hepatoblastomas, with mutations in the APC and b-catenin genes implicated in familial adenomatous polyposis-associated and sporadic hepatoblastomas, respectively. Alterations in other cancer-related molecular pathways have not been reported. We investigated a series of 21 sporadic paraffin-embedded hepatoblastoma cases for mutations in the p53 (exons 5-8) and b-catenin (exon 3) genes, loss of heterozygosity at APC, microsatellite instability and immunohistochemical expression of b-catenin and of the two main mismatch repair proteins, MLH1 and MSH2. No loss of heterozygosity at APC was detected. We found mutations in b-catenin and p53 in 4/21 (19%) and 5/21 (24%) cases respectively, b-catenin protein accumulation in 14/21 cases (67%), microsatellite instability in 17/21 cases (81%), of which eight resulted positive for high-level of microsatellite instability (in four cases associated with loss of MLH1/MSH2 immunostaining). No correlations between involved molecular pathway(s) and hepatoblastoma histotype(s) emerged. This study confirms that b-catenin deregulation is involved in sporadic hepatoblastoma and also suggests that mismatch repair defects and p53 mutations contribute to this rare liver cancer. Sporadic hepatoblastoma appears to be molecularly and phenotypically heterogeneous and may reflect different pathways of liver carcinogenesis.

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“…Canonical Wnt signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the β-catenin signaling cascade (comprehensively reviewed by Wend et al, 2010). This Wnt/β-catenin signaling pathway is important for self-renewal in stem cells and has been found to be dysregulated in solid and haematopoietic cancers Katoh & Katoh, 2007). The pathway has also been shown to promote genomic instability, thereby enhancing the DNA damage tolerance in CSCs (Eyler & Rich, 2008).…”

Section: Wnt/β-cateninmentioning

confidence: 99%