Secreted Frizzled-Related Protein 4 Inhibits Glioma Stem-Like Cells by Reversing Epithelial to Mesenchymal Transition, Inducing Apoptosis and Decreasing Cancer Stem Cell Properties

Bhuvanalakshmi, G; Arfuso, Frank; Millward, Michael; Dharmarajan, Arun; Warrier, Sudha

doi:10.1371/journal.pone.0127517

Cited by 55 publications

(42 citation statements)

References 47 publications

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“…Among these genes, CDH1 and Notch-1 (Figure 4A) are regarded as the regulators of Wnt/β-catenin and PI3K/Akt signaling pathways, respectively [21,22]. As the two pathways are always activated in glioma cells and GSCs [23,24,25,26], we hypothesize that CDH1 and Nocth-1 could be the direct targets of miR-92a. To test our hypothesis, qRT-PCR and Western blotting assay were applied to measure the relative expression levels of CDH1 and Notch-1 in two cell types.…”

Section: Resultsmentioning

confidence: 99%

miR-92a-3p Exerts Various Effects in Glioma and Glioma Stem-Like Cells Specifically Targeting CDH1/β-Catenin and Notch-1/Akt Signaling Pathways

Song

Zhang

Liu

et al. 2016

IJMS

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MicroRNAs (miRNAs) are implicated in the regulation of tumor progression and stemness of cancer stem-like cells. Recently, miR-92a-3p was reported to be up-regulated in human glioma samples. Nevertheless, the precise role of miR-92a-3p in glioma cells and glioma stem-like cells (GSCs) has not been fully elucidated. It is necessary to clarify the function of miR-92a-3p in glioma and GSCs to develop novel therapeutic approaches for glioma patients. In the present study, we applied methyl-thiazolyl-tetrazolium (MTT) assay and Transwell assay to measure the proliferation rate and metastatic potential of glioma cells. Meanwhile, the self-renewal ability of GSCs was detected by tumor sphere formation assay. The results revealed that down-regulation of miR-92a-3p suppressed the glioma cell malignancy in vitro. Moreover, knockdown of miR-92a-3p led to a reduction of tumorgenesis in vivo. Interestingly, we also observed that up-regulation of miR-92a-3p could inhibit the stemness of GSCs. Subsequent mechanistic investigation indicated that cadherin 1 (CDH1)/β-catenin signaling and Notch-1/Akt signaling were the downstream pathways of miR-92a-3p in glioma cells and GSCs, respectively. These results suggest that miR-92a-3p plays different roles in glioma cells and GSCs through regulating different signaling pathways.

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Section: Resultsmentioning

confidence: 99%

miR-92a-3p Exerts Various Effects in Glioma and Glioma Stem-Like Cells Specifically Targeting CDH1/β-Catenin and Notch-1/Akt Signaling Pathways

Song

Zhang

Liu

et al. 2016

IJMS

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“…Three breast cancer cell lines MDA-MB-231, T47D and MCF7 (NCCS, Pune, India) were enriched for bCSCs by growing as mammospheres in growth factor enriched serum-free medium (SFM) as reported previously (Bhuvanalakshmi et al, 2015) in basal medium (DMEM/F-12 + DMEM-HG) with 100 U/mL PenStrep, 2mM GlutaMAX, and containing 20 ng/mL each of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF; R&D Systems), and leukemia inhibitory factor (LIF; Chemicon). All cells were cultured at 37°C in a humid incubator with 5% CO2.…”

Section: Methodsmentioning

confidence: 99%

“…All cells were cultured at 37°C in a humid incubator with 5% CO2. MTT was performed as described previously (Bhuvanalakshmi et al, 2015) using DG (Sigma–Aldrich, St. Louis, MO, USA) at concentrations 0–500 μM. After determining the IC50 value at 400 μM after 24 h, the subsequent experiments were at this concentration of DG for 24 h. BrdU and caspase assays were performed as described previously (Bhuvanalakshmi et al, 2014) with bCSCs from MDA-MB-231 and T47D.…”

Section: Methodsmentioning

confidence: 99%

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Breast Cancer Stem-Like Cells Are Inhibited by Diosgenin, a Steroidal Saponin, by the Attenuation of the Wnt β-Catenin Signaling via the Wnt Antagonist Secreted Frizzled Related Protein-4

et al. 2017

Self Cite

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Background: Identification of breast cancer stem cells as the chemo-resistant and tumor-initiating population represents an important milestone in approaching anticancer therapies. Targeting this minor subpopulation of chemo- and radio-resistant stem-like cells, termed as the cancer stem cells (CSCs) and their eradication could significantly enhance clinical outcomes. Most of the presently administered chemotherapeutics target the tumor bulk but are ineffective against the CSCs. We report here that diosgenin (DG), a naturally occurring steroidal saponin, could effectively inhibit CSCs from three breast cancer cell lines, MCF7, T47D and MDA-MB-231, by inducing apoptosis and inhibiting the CSC associated phenotypes.Methods: CSCs were enriched in these cells lines, characterized for CSC traits by immunocytochemistry and flow cytometry. Proliferation and apoptosis assays were performed in these breast CSCs in the presence of DG to obtain the inhibitory concentration. Apoptosis was confirmed with gene expression analysis, Western blotting and propidium iodide staining. TCF-LEF reporter assay, sFRP overexpression and RNAi silencing studies were performed to study regulation of the Wnt pathway. Statistical significance was evaluated by a two-sided Student’s t-test.Results: Using the TCF-LEF reporter system, we show the effect of DG on CSCs is predominantly through the network regulating CSC self renewal, the Wnt β-catenin pathway. Specifically, the Wnt antagonist, the secreted frizzled related protein 4, (sFRP4), had a defining role in the action of DG. Gain-of-function of sFRP4 in CSCs could improve the response to DG wherein CSC mediators were inhibited, β-catenin was down regulated and the effectors of epithelial to mesenchymal transition and pro-invasive markers were repressed. Conversely, the loss-of-function of sFRP4 had a reverse effect on the CSC population which therein became enriched, their response to DG treatment was modest, β-catenin levels increased, GSK3β expression decreased and the expression of epithelial markers of CSC was completely abrogated.Conclusion: These findings demonstrate the effect of DG on inhibiting the resilient breast CSCs which could provide a benchmark for the development of DG-based therapies in breast cancer treatment.

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“…In the present study, we demonstrated that silencing SFRP4 inhibited eWAT preadipocyte differentiation; in contrast, SFRP4 silencing promoted iWAT preadipocyte differentiation through the induction of adipocyte differentiation progression. Although SFRP4 has been shown to play an important role in several types of disease [32-34], the expression and function of SFRP4 in eWAT adipocyte development has not been fully investigated. In the current report, we first observed that SFRP4 expression was increased upon the induction of differentiation in eWAT preadipocytes.…”

Section: Discussionmentioning

confidence: 99%

Differential Patterns of Secreted Frizzled-Related Protein 4 (SFRP4) in Adipocyte Differentiation: Adipose Depot Specificity

Guan

Zhang

Gao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that acts as soluble modulators of Wnt signaling. Given the substantial rise in obesity, depot-specific fat accumulation and its associated diseases like diabetes, it is important to understand the molecular basis of depot-specific adipocyte differentiation. In the current study, we investigated the expression of SFRP4 in both subcutaneous and visceral adipose tissue in terms of their differentiation. Methods: White preadipocytes were isolated from the inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) from C57BL/6J mice (age: 8-week-old, male). SFRP4 expression in iWAT and eWAT preadipocytes was silenced by siRNA transfection and harvested cells for gene and protein expression analysis was performed during the differentiation. Furthermore, iWAT and eWAT preadipocytes treated with or without IL-1β were harvested for gene and protein expression analysis. Results: SFRP4 expression levels were gradually increased and proportionally associated with eWAT adipocyte differentiation toward maturation at 14 days, while iWAT adipocyte just showed an opposite tendency. Moreover, genetic (adiponectin, C/EBPα, C/EBPβ, FABP4, GLUT4 and PPARγ) analysis demonstrated that depot-specific adipogenesis in response to SFRP4 silencing in eWAT and iWAT preadipocytes. Upon IL-1β treatment, SFRP4 mRNA expression decreased significantly in iWAT adipocyte, but the expression was no significant difference in eWAT adipocyte. Conclusion: These results suggest that SFRP4 expression differentially mediates adipocyte differentiation and may play an important role in adipogenesis.

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Secreted Frizzled-Related Protein 4 Inhibits Glioma Stem-Like Cells by Reversing Epithelial to Mesenchymal Transition, Inducing Apoptosis and Decreasing Cancer Stem Cell Properties

Cited by 55 publications

References 47 publications

miR-92a-3p Exerts Various Effects in Glioma and Glioma Stem-Like Cells Specifically Targeting CDH1/β-Catenin and Notch-1/Akt Signaling Pathways

miR-92a-3p Exerts Various Effects in Glioma and Glioma Stem-Like Cells Specifically Targeting CDH1/β-Catenin and Notch-1/Akt Signaling Pathways

Breast Cancer Stem-Like Cells Are Inhibited by Diosgenin, a Steroidal Saponin, by the Attenuation of the Wnt β-Catenin Signaling via the Wnt Antagonist Secreted Frizzled Related Protein-4

Differential Patterns of Secreted Frizzled-Related Protein 4 (SFRP4) in Adipocyte Differentiation: Adipose Depot Specificity

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