Wnt signaling and astrocytic brain tumors

Pećina‐Šlaus, Nives; Kafka, Anja

doi:10.2217/cns.15.24

Cited by 5 publications

(3 citation statements)

References 20 publications

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“…Collective results of our previous work have shown that glioma proliferation and invasion are fueled by Wnt signaling activation ( Pećina-Šlaus et al, 2014 ; Kafka et al, 2019 ). We have found that promoters of selected genes displayed different methylation frequencies ( Pećina-Šlaus et al, 2011 ; Kafka et al, 2017 , 2021 ).…”

Section: Discussionmentioning

confidence: 99%

SFRP4 protein expression is reduced in high grade astrocytomas which is not caused by the methylation of its promoter

Kafka,

Pećina-Šlaus,

Drmić

et al. 2024

Front. Mol. Neurosci.

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IntroductionEpigenetics play a vital role in stratifying CNS tumors and gliomas. The importance of studying Secreted frizzled-related protein 4 (SFRP4) in gliomas is to improve diffuse glioma methylation profiling. Here we examined the methylation status of SFRP4 promoter and the level of its protein expression in diffuse gliomas WHO grades 2–4.MethodsSFRP4 expression was detected by immunohistochemistry and evaluated semi-quantitatively. In the tumor hot-spot area, the intensity of protein expression in 200 cells was determined using ImageJ (National Institutes of Health, United States). The assessment of immunopositivity was based on the IRS score (Immunoreactivity Score). Promoter methylation was examined by methylation specific-PCR (MSP) in fifty-one diffuse glioma samples and appropriate controls. Isolated DNA was treated with bisulfite conversion and afterwards used for MSP. Public databases (cBioPortal, COSMIC and LOVD) were searched to corroborate the results.Results and discussionSFRP4 protein expression in glioblastomas was very weak or non-existent in 86.7% of samples, moderate in 13.3%, while strong expression was not observed. The increase in astrocytoma grade resulted in SFRP4 protein decrease (p = 0.008), indicating the loss of its antagonistic role in Wnt signaling. Promoter methylation of SFRP4 gene was found in 16.3% of cases. Astrocytomas grade 2 had significantly more methylated cases compared to grade 3 astrocytomas (p = 0.004) and glioblastomas (p < 0.001), which may indicate temporal niche of methylation in grade 2. Furthermore, the expression levels of SFRP4 were high in samples with methylated SFRP4 promoter and low or missing in unmethylated cases (Pearson’s R = −0.413; p = 0.003). We also investigated the association of SFRP4 changes to key Wnt regulators GSK3β and DKK3 and established a positive correlation between methylations of SFRP4 and GSK3β (Pearson’s R = 0.323; p = 0.03). Furthermore, SFRP4 expression was correlated to unmethylated DKK3 (Chi square = 7.254; p = 0.027) indication that Wnt signaling antagonist is associated to negative regulator’s demethylation.ConclusionThe study contributes to the recognition of the significance of epigenetic changes in diffuse glioma indicating that restoring SFRP4 protein holds potential as therapeutic avenue. Reduced expression of SFRP4 in glioblastomas, not following promoter methylation pattern, suggests another mechanism, possible global methylation, that turns off SFRP4 expression in higher grades.

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Section: Discussionmentioning

confidence: 99%

SFRP4 protein expression is reduced in high grade astrocytomas which is not caused by the methylation of its promoter

Kafka,

Pećina-Šlaus,

Drmić

et al. 2024

Front. Mol. Neurosci.

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“…The investigation on three human Disheveled genes (DVL1, DVL2 and DVL3) evidenced on their association to transcription factors LEF1 and TCF1 influencing their important roles in glial branch of brain tumors [124]. Additional findings indicated that transcription factors of the Wnt pathway, TCF1 and LEF1, were upregulated in malignant high-grade gliomas [125]. The investigation on secreted frizzledrelated protein 3 (SFRP3) showed its modulation of the Wnt signaling cascade [126], and its expression levels suggested its dual role in Wnt signaling depending on the context.…”

Section: Signaling Pathways In Glioma Cancer Stem Cellsmentioning

confidence: 98%

Glioma Stem Cells—Features for New Therapy Design

Pećina-Šlaus,

Hrašćan

2024

Cancers

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On a molecular level, glioma is very diverse and presents a whole spectrum of specific genetic and epigenetic alterations. The tumors are unfortunately resistant to available therapies and the survival rate is low. The explanation of significant intra- and inter-tumor heterogeneity and the infiltrative capability of gliomas, as well as its resistance to therapy, recurrence and aggressive behavior, lies in a small subset of tumor-initiating cells that behave like stem cells and are known as glioma cancer stem cells (GCSCs). They are responsible for tumor plasticity and are influenced by genetic drivers. Additionally, GCSCs also display greater migratory abilities. A great effort is under way in order to find ways to eliminate or neutralize GCSCs. Many different treatment strategies are currently being explored, including modulation of the tumor microenvironment, posttranscriptional regulation, epigenetic modulation and immunotherapy.

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“…Wnt-signaling pathways are evolutionarily conserved, and secreted Wnt/Wg proteins activate a variety of signal transduction events across all metazoans 4,6,7 . Wnt signaling is also one of the key pathways closely related to several diseases, including the initiation and progression of various types of cancers [8][9][10][11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Wg/Wnt-signaling induced nuclear translocation of β-catenin is attenuated by a β-catenin peptide through its interaction with IFT-A in development and cancer cells

Vuong

Mlodzik

2023

Preprint

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Wnt/Wingless (Wg) signaling is critical for many developmental patterning processes and linked to diseases, including cancer. Canonical Wnt-signaling is mediated by β-catenin, Armadillo/Arm in Drosophila transducing signal activation to a nuclear response. The IFT-A/Kinesin-2 complex is required to promote the nuclear translocation of β-catenin/Arm. Here, we define a small conserved N-terminal Arm/β-catenin (Arm34-87) peptide, which binds IFT140, as a dominant interference tool to attenuate Wg/Wnt-signaling in vivo. Expression of Arm34-87 is sufficient to antagonize endogenous Wnt/Wg-signaling activation resulting in marked reduction of Wg-signaling target gene expression. This effect is modulated by endogenous levels of Arm and IFT140, with the Arm34-87 effect being enhanced or suppressed, respectively. Arm34-87 thus inhibits Wg/Wnt-signaling by interfering with the nuclear translocation of endogenous Arm/β-catenin. Importantly, this mechanism is conserved in mammals with the equivalent β-catenin34-87 peptide blocking nuclear translocation and pathway activation, including in cancer cells. Our work indicates that Wnt-signaling can be regulated by a defined N-terminal peptide of Arm/β-catenin, and thus this might serve as an entry point for potential therapeutic applications to attenuate Wnt/β-catenin signaling.

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Wnt signaling and astrocytic brain tumors

Cited by 5 publications

References 20 publications

SFRP4 protein expression is reduced in high grade astrocytomas which is not caused by the methylation of its promoter

SFRP4 protein expression is reduced in high grade astrocytomas which is not caused by the methylation of its promoter

Glioma Stem Cells—Features for New Therapy Design

Wg/Wnt-signaling induced nuclear translocation of β-catenin is attenuated by a β-catenin peptide through its interaction with IFT-A in development and cancer cells

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