Activation of Wnt/β-catenin/Tcf signaling pathway in human astrocytomas

Sareddy, Gangadhara R.; Panigrahi, Manas; Challa, Sundaram; Mahadevan, Anita; Babu, Phanithi Prakash

doi:10.1016/j.neuint.2009.03.016

Cited by 110 publications

(105 citation statements)

References 40 publications

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“…expression was observed in gliomas, including astrocytomas and GBMs. 20 Furthermore, Wnt/b-catenin signaling is regulated by PLAGL2 and FoxM1 proto-oncogenes during gliomagenesis. 18,22 Here, we identified PY142 b-catenin as a nuclear b-catenin form that signals through transcriptional regulation in GBM.…”

Section: Resultsmentioning

confidence: 99%

“…10,[13][14][15][16] Although activating mutations of b-catenin have not been identified in GBM 17 , overexpression of b-catenin and other Wnt pathway components (including Fz 18 ) together with epigenetic regulation of Wnt inhibitors results in Wnt/ b-catenin activation in GBM. [19][20][21] Overexpression of the Forkhead box M1 (FoxM1) transcription factor represents a critical mechanism further contributing to b-catenin signaling in GBM. 22 FoxM1 promotes b-catenin nuclear accumulation and together they form a complex with TCF4 required for glioma stem cell self-renewal and gliomagenesis.…”

Section: Introductionmentioning

confidence: 99%

“…33 Here we studied the role of b-catenin phosphorylated at Y142 (PY142) in cell invasion in GBM, a tumor in which total and dephospho S/T b-catenin (a classical Wnt transducer; hereon active b-catenin) have already received some attention. 20,34,35 We used GBM biopsies, cell lines and cell cultures established from tumoral tissue. Our findings identify a nuclear pool of PY142 b-catenin in GBM cells.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glialderived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/b-catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that b-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) b-catenin and dephospho S/T b-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsyderived glioma cell cultures. We found that PY142 b-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 b-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active b-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active b-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 b-catenin and Snail/Slug. Importantly, the expression of mutant Y142F b-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 b-catenin as a nuclear b-catenin signaling form that downregulates adhesion and promotes GBM cell invasion.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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“…4 They are also higher in high ¼ grade tumors than in low-grade tumors. 2,4 Moreover, cytoplasmic/nuclear b-catenin and …”

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confidence: 99%

“…Recently, several reports showed a relationship between the WNT signaling pathway and the grade and prognosis of astrocytomas. [2][3][4] Both mRNA and protein expression levels of b-catenin are increased in astrocytoma compared with normal brain tissue. 4 They are also higher in high ¼ grade tumors than in low-grade tumors.…”

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confidence: 99%

Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/β-catenin pathway in human astrocytoma: pathologic and prognostic correlations

et al. 2013

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WNT inhibitory factor-1 (WIF1) is an antagonist of the WNT signaling pathway. We investigated the relationship between WIF1 promoter methylation and regulation of the WNT/b-catenin signaling pathway, tumor grade, and survival in patients with astrocytoma. This study included 86 cases of astrocytoma, comprising 20 diffuse astrocytomas and 66 glioblastomas. In addition, 17 temporal lobectomy specimens from patients with epilepsy were included as controls. The ratio of methylated DNA to total methylated and unmethylated DNA (% methylation) was measured by methylation-and unmethylation-specific PCR. Representative tumor tissue was immunostained for WIF1, b-catenin, cyclin D1, c-myc, and isocitrate dehydrogenase 1. Levels of WIF1 promoter methylation, mRNA expression, and protein expression in a glioblastoma cell line were compared before and after demethylation treatment. The mean percent methylation of the WIF1 promoter in astrocytomas was higher than that in control brain tissue. WIF1 protein expression was lower in the tumor group with 45% methylation than in the group with o5% methylation. Cytoplasmic b-catenin staining was more frequently observed in tumors with a low WIF1 protein expression level. Demethylation treatment of a glioblastoma cell line increased WIF1 mRNA and protein expression. Increased WIF1 promoter methylation and decreased WIF1 protein expression were not related to patient survival. In conclusion, WIF1 expression is downregulated by promoter methylation and is an important mechanism of aberrant WNT/b-catenin pathway activation in astrocytoma pathogenesis. Modern Pathology (2013) 26, 626-639; doi:10.1038/modpathol.2012.215; published online 18 January 2013Keywords: astrocytoma; b-catenin; glioblastoma; promoter methylation; WNT inhibitory factor-1; WNT pathway Astrocytomas are the most common primary tumors of the central nervous system. Despite aggressive treatment with surgery and subsequent chemoradiotherapy, high-grade astrocytomas show a high rate of recurrence and mortality. 1 Understanding the molecular basis of astrocytoma tumorigenesis is necessary for prediction of therapy response, prognosis, and the development of more effective therapies. Recently, several reports showed a relationship between the WNT signaling pathway and the grade and prognosis of astrocytomas. [2][3][4] Both mRNA and protein expression levels of b-catenin are increased in astrocytoma compared with normal brain tissue. 4 They are also higher in high ¼ grade tumors than in low-grade tumors. 2,4 Moreover, cytoplasmic/nuclear b-catenin and

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CNSCancers

Graeme

2010

Burger's Medicinal Chemistry and Drug Discovery

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CNS tumors represent a diverse collection of tumor types driven by a range of signaling inputs that often generate highly aggressive and at the same time heterogeneous tumor types. The effect of these tumors is particularly dramatic and impacts on children as well as adults. Malignant CNS tumors are characterized by being highly heterogeneous, aggressive, and frequently invasive, leading to poor overall patient survival times. As CNS tumors present within the nervous system, there are particular challenges in the development of effective molecular‐targeted therapies in dealing not only with the aggressive nature of these tumors and their ability to evade treatment but also, particularly, with maintaining normal neuronal and brain functions. Compounding this is the need to deliver systemically small molecules or other agents such as vaccines and for immunotherapy approaches to confront the complexity of the relationship between the nervous system and the immune system. Research to find effective treatments for CNS tumors is being facilitated by two key inputs both of which are reviewed in this chapter; first, a much greater understanding of tumor pathobiology and the potential role of developmental signaling pathways and tumor stem‐like cells, and by the development of animal models that more adequately represent endpoints measurable in the clinic. Together, these advances should assist in the selection of better targets and the optimization of better compounds to progress into clinical trials.

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Activation of Wnt/β-catenin/Tcf signaling pathway in human astrocytomas

Cited by 110 publications

References 40 publications

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/β-catenin pathway in human astrocytoma: pathologic and prognostic correlations

CNSCancers

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