Activated β-catenin Forces N2A Cell-derived Neurons Back to Tumor-like Neuroblasts and Positively Correlates with a Risk for Human Neuroblastoma

Zhi, Feng; Gong, Guangming; Xu, Yan; Zhu, Yan; Hu, Die; Yang, Yilin; Hu, Yiqiao

doi:10.7150/ijbs.3520

Cited by 16 publications

(20 citation statements)

References 28 publications

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“…MYC expression is dependent upon Wnt/β-catenin signaling [30]. Previous studies have implicated a potential relationship between increased Wnt/β-catenin signaling and neuroblastoma [15, 31, 32]. Likewise, we provide evidence for Wnt/FZD2 activity in high-risk NB cell lines by showing increased phospho-LRP6 and active β-catenin levels in NB cells treated with recombinant Wnt3a, consistent with canonical β-catenin signaling.…”

Section: Discussionsupporting

confidence: 80%

“…Together with the observed downregulation of β-catenin target genes this further strengthens our hypothesis that activation of the β-catenin pathway by FZD2 promotes growth of high-risk NBs. This is also supported by the finding that expression of β-catenin was involved in maintaining a neuroblast-like phenotype of NB cells [32]. However, based on the complexity of the involved pathways and the expression of FZD3 on both NB cell lines, we assume that the growth promoting effect of FZD2 in high-risk NB is the consequence from complex interactions between different pathways (Figure 6).…”

Section: Discussionsupporting

confidence: 57%

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Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways

et al. 2016

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Frizzled2 (FZD2) is a receptor for Wnts and may activate both canonical and non-canonical Wnt signaling pathways in cancer. However, no studies have reported an association between FZD2 signaling and high-risk NB so far. Here we report that FZD2 signaling pathways are critical to NB growth in MYCN-single copy SK-N-AS and MYCN-amplified SK-N-DZ high-risk NB cells. We demonstrate that stimulation of FZD2 by Wnt3a and Wnt5a regulates β-catenin-dependent and –independent Wnt signaling factors. FZD2 blockade suppressed β-catenin-dependent signaling activity and increased phosphorylation of PKC, AKT and ERK in vitro, consistent with upregulation of β-catenin-independent signaling activity. Finally, FZD2 small interfering RNA knockdown suppressed tumor growth in murine NB xenograft models associated with suppressed β-catenin-dependent signaling and a less vascularized phenotype in both NB xenografts. Together, our study suggests a role for FZD2 in high-risk NB cell growth and provides a potential candidate for therapeutic inhibition in FZD2-expressing NB patients.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 57%

Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways

et al. 2016

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“…Western blotting analysis was performed using conventional protocols as previously described [26]. Briefly, the rabbit monoclonal β-actin antibody (Cell Signaling Technology, USA), rabbit polyclonal FASTK antibody (Abcam, UK), and the secondary rabbit IgG-HRP (Sigma, USA) were applied at 1∶1,000, 1∶500, and 1∶5,000 dilutions, respectively.…”

Section: Methodsmentioning

confidence: 99%

miR-106a-5p Inhibits the Proliferation and Migration of Astrocytoma Cells and Promotes Apoptosis by Targeting FASTK

et al. 2013

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Astrocytomas are common malignant intracranial tumors that comprise the majority of adult primary central nervous system tumors. MicroRNAs (miRNAs) are small, non-coding RNAs (20–24 nucleotides) that post-transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. In our previous studies, we found that the downregulation of miR-106a-5p in astrocytomas is associated with poor prognosis. However, its specific gene target(s) and underlying functional mechanism(s) in astrocytomas remain unclear. In this study, we used mRNA microarray experiments to measure global mRNA expression in the presence of increased or decreased miR-106a-5p levels. We then performed bioinformatics analysis based on multiple target prediction algorithms to obtain candidate target genes that were further validated by computational predictions, western blot analysis, quantitative real-time PCR, and the luciferase reporter assay. Fas-activated serine/threonine kinase (FASTK) was identified as a direct target of miR-106a-5p. In human astrocytomas, miR-106a-5p is downregulated and negatively associated with clinical staging, whereas FASTK is upregulated and positively associated with advanced clinical stages, at both the protein and mRNA levels. Furthermore, Kaplan-Meier analysis revealed that the reduced expression of miR-106a-5p or the increased expression of FASTK is significantly associated with poor survival outcome. These results further supported the finding that FASTK is a direct target gene of miR-106a-5p. Next, we explored the function of miR-106a-5p and FASTK during astrocytoma progression. Through gain-of-function and loss-of-function studies, we demonstrated that miR-106a-5p can significantly inhibit cell proliferation and migration and can promote cell apoptosis in vitro. The knockdown of FASTK induced similar effects on astrocytoma cells as those induced by the overexpression of miR-106a-5p. These observations suggest that miR-106a-5p functions as a tumor suppressor during the development of astrocytomas by targeting FASTK.

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“…Other studies have also shown that aberrant activation of this pathway is induced by dysregulation of Wnt pathway members or by downregulation of endogenous Wnt antagonists [7][8][9]. Aberrant expression of Wnt/β-catenin signaling is known to play a significant role in various processes of early development and in the pathogenesis of adult and pediatric tumors including neuroblastoma [10,11].…”

Section: Introductionmentioning

confidence: 99%

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

et al. 2014

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Neuroblastoma is the most common extracranial solid tumor in childhood and is associated with serious morbidity and mortality. The effective treatment of neuroblastoma remains one of the major challenges in pediatric oncology. The Wnt signaling pathway has been shown to play a significant role in the pathogenesis of adult and pediatric tumors. WIF-1 has been identified as an important Wnt antagonist which inhibits Wnt/β-catenin signaling by directly binding to Wnt proteins. However, the expression and function of WIF-1 in neuroblastoma remains unknown. The present study showed that WIF-1 was downregulated with high level promoter methylation in neuroblastoma cells, and was significantly upregulated after exposure to demethylating agent. This finding suggests that downregulation of WIF-1 was associated with its promoter methylation in neuroblastoma. To further study the potential function of WIF-1 in neuroblastoma, we constructed a plasmid that over-expressed WIF-1 and transfected the plasmid into one neuroblastoma cell line SK-N-SH. We found that restoration of WIF-1 inhibited the growth and proliferation of neuroblastoma cells in vitro. Morever, Wnt/β-catenin signaling activity and target genes expression were reduced by WIF-1 restoration. These results provide support that WIF-1 is downregulated and functions as a tumor suppressor by antagonizing Wnt/β-catenin signaling in neuroblastoma, suggesting a potential role as a therapeutic target in neuroblastoma.

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Activated β-catenin Forces N2A Cell-derived Neurons Back to Tumor-like Neuroblasts and Positively Correlates with a Risk for Human Neuroblastoma

Cited by 16 publications

References 28 publications

Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways

Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways

miR-106a-5p Inhibits the Proliferation and Migration of Astrocytoma Cells and Promotes Apoptosis by Targeting FASTK

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

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