Targeting Wnt/β-catenin signaling by microRNAs as a therapeutic approach in chemoresistant osteosarcoma

Hosseini, Foroogh; Alemi, Forough; Malakoti, Faezeh; Mahmoodpoor, Ata; Younesi, Simin; Yousefi, Bahman; Asemi, Zatollah

doi:10.1016/j.bcp.2021.114758

Cited by 21 publications

(12 citation statements)

References 108 publications

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“…We thus speculate that chemoresistant cell lines might be more dependent on Wnt/β-catenin than sensitive lines. This speculation is supported by previous findings that β-catenin signalling is essential in chemo-resistant osteosarcoma, and targeting β-catenin is a therapeutic approach to sensitize osteosarcoma cells to chemotherapy (Ma et al, 2013;Hosseini et al, 2021). Although the activity of β-catenin and level of MYC were not lower in chemoresistant cell lines after niclosamide treatment than parental cell lines, the reduction of β-catenin activity and MYC level by niclosamide in chemoresistant cells is sufficient to inhibit growth and survival.…”

Section: Discussionsupporting

confidence: 65%

“…Several studies indicated that niclosamide targets β-catenin to inhibit cancer cells ( Arend et al, 2016 ; Jin et al, 2017 ; Wei et al, 2021 ; Guo et al, 2022 ). Given the importance of Wnt/β-catenin in osteosarcoma progression and chemoresistance ( Ma et al, 2013 ; Hosseini et al, 2021 ), we investigated whether niclosamide acts on osteosarcoma via inhibiting Wnt/β-catenin. We measured β-catenin level and activity in osteosarcoma cells after niclosamide treatment.…”

Section: Resultsmentioning

confidence: 99%

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Niclosamide is a potential candidate for the treatment of chemo-resistant osteosarcoma

Huang

Wang

2023

Genet. Mol. Biol.

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Chemotherapy is the main treatment option for advanced osteosarcoma, which is the most common type of primary bone malignancy. However, patients develop resistance rapidly and many succumb to the disease. Niclosamide, an anthelmintic drug, has been recently identified to display potent and selective anti-cancer activity. In this work, we show that niclosamide at sub-micromolar concentrations inhibits proliferation and migration, and induces apoptosis in both parental and chemo-resistant osteosarcoma cells, with much less toxicity in normal osteoblastic cells. Interestingly, chemo-resistant osteosarcoma cells are more sensitive to niclosamide compared to parental cells. We further identify that inhibition of β-catenin is the underlying mechanism of niclosamide’s action in osteosarcoma cells. In addition, we reveal that chemo-resistant osteosarcoma cells display increased β-catenin activity compared to parental cells, which might explain the hypersensitivity of chemo-resistant cells to niclosamide. Our work provides pre-clinical evidence that niclosamide can be repurposed for treating osteosarcoma. Our findings also suggest the therapeutic value of β-catenin to overcome osteosarcoma chemo-resistance.

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Section: Discussionsupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Niclosamide is a potential candidate for the treatment of chemo-resistant osteosarcoma

Huang

Wang

2023

Genet. Mol. Biol.

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“…Accumulated research data showed that miRNAs were important regulators in cancer progression by regulating cell functions in various cancers, including OS [11,14]. In addition, studies have analyzed the expression of miR-NAs in OS plasma samples in the Gene Expression Comprehensive database and found that the expression of miRNAs in OS patients was abnormally expressed when comparing with the controls [26].…”

Section: Discussionmentioning

confidence: 99%

Circ-NT5C2 stimulates FZD4 expression to promote the malignant progression of osteosarcoma by targeting miR-488-3p

et al. 2022

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Background Circ-NT5C2 has been confirmed to be highly expressed and associated to the progression of osteosarcoma (OS). However, the behind mechanism of circ-NT5C2 involvement in OS remains unclear. Methods The expression of circ-NT5C2, miR-488-3p and FZD4 was measured by quantitative real-time PCR, and the protein expression of E-cadherin, N-cadherin and FZD4 was detected by western blot. Cell counting kit 8 assay, colony formation assay and 5-ethynyl-2-deoxyuridine assay were performed to assess the cell proliferation. The cell apoptosis was measured by flow cytometry and Caspase3/Caspase9 Activity Assay Kits. Cell migration and invasion were detected by transwell assay. Dual-luciferase reporter assay and RIP assay were carried out to determine the binding relation among circ-NT5C2, miR-488-3p and FZD4. Animal experiment and immunohistochemistry analysis were conducted to explore the role of circ-NT5C2 in tumor growth in vivo. Results Comparing with controls, the expression of circ-NT5C2 and FZD4 was upregulated and miR-488-3p expression was downregulated in OS tumor tissues and cells. Circ-NT5C2 overexpression facilitated the cell proliferation and motility and induced cell apoptosis of OS cells, whereas circ-NT5C2 knockdown had the opposite effect. Besides, we also found and confirmed that circ-NT5C2 regulated cell malignant behaviors via modulating miR-488-3p/FZD4 axis in OS. Moreover, circ-NT5C2 silencing repressed the growth of xenografts in vivo. Conclusion Circ-NT5C2 upregulated FZD4 expression via sponging miR-488-3p, thus facilitating cell malignant behaviors in OS.

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“…62,63 Besides, AXIN2 is a negative regulator of the WNT/β-catenin pathway, inhibiting β-catenin accumulation. 64 As the β-catenin gene is highly expressed, the AXIN2 gene expression would also increase to maintain the stable β-catenin content.…”

Section: T H Imentioning

confidence: 99%

Vanadium-Doped Mesoporous Bioactive Glass Promotes Osteogenic Differentiation of rBMSCs via the WNT/β-Catenin Signaling Pathway

Cong,

Zhang,

et al. 2023

ACS Appl. Bio Mater.

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Pentavalent vanadium [V(V)] has been studied as bioactive ions to improve the bone defect repair; however, its osteogenic promotion mechanism is still not fully understood so far. In this study, a V-doped mesoporous bioactive glass (V-MBG) was prepared, and its effects on osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) and potential signaling pathways were investigated. The physicochemical characterization revealed that the incorporation of V slightly reduced the specific surface area and increased the mesoporous pore size, and the abundant mesopores of V-MBG were beneficial to the sustained dissolution of V(V) ions as well as calcium, silicon, and phosphorus ions. Cell proliferation results indicated that the high dilution ratio (>16) V-MBG extract markedly promoted the proliferation of rBMSCs compared with the control group and the same dilution ratio MBG extract. Compared with the same dilution ratio MBG extract, diluted V-MBG extracts markedly promoted the secretion of alkaline phosphatase (ALP) and osteocalcin (OCN) protein at day 7 but insignificantly stimulated the runt-related transcription factor 2 (RUNX2) and vascular endothelial growth factor (VEGF) protein synthesis. In depth, the diluted V-MBG extracts remarkably up-regulated the expression of WNT/β-catenin pathway direct target genes, including WNT3a, β-catenin, and AXIN2 genes in contrast to the same dilution ratio MBG extracts, suggesting that the released V(V) ions might promote osteogenic differentiation of rBMSCs via the WNT/β-catenin signaling pathway.

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Targeting Wnt/β-catenin signaling by microRNAs as a therapeutic approach in chemoresistant osteosarcoma

Cited by 21 publications

References 108 publications

Niclosamide is a potential candidate for the treatment of chemo-resistant osteosarcoma

Niclosamide is a potential candidate for the treatment of chemo-resistant osteosarcoma

Circ-NT5C2 stimulates FZD4 expression to promote the malignant progression of osteosarcoma by targeting miR-488-3p

Vanadium-Doped Mesoporous Bioactive Glass Promotes Osteogenic Differentiation of rBMSCs via the WNT/β-Catenin Signaling Pathway

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