Inhibition of the invasion of human glioblastoma u87 cell line by ruxolitinib: a molecular player of mir-17 and mir-20a regulating jak/stat pathway

Delen, Emre; Doğanlar, Oğuzhan; Doğanlar, Zeynep Banu; Delen, Özlem

doi:10.5137/1019-5149.jtn.26122-19.1

Cited by 9 publications

(7 citation statements)

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“…Interestingly, pacritinib was also shown to decrease the amount of miR-21enriched exosomes released from tumor-associated macrophages, reducing an exogenous source of STAT3 upregulation in glioma cells [94]. Ruxolitinib not only decreased the invasiveness of GBM cells but also was found to be able to inhibit the compensatory JAK1/STAT1 signaling that limits the efficacy of oncolytic virotherapy [219][220][221]. Ruxolitinib is currently being evaluated in a phase I trial for patients with newly diagnosed MGMT-unmethylated malignant glioma in combination with radiation and temozolomide (NCT03514069).…”

Section: Pharmaceutical Inhibition Of Stat3: Jak Inhibitorsmentioning

confidence: 99%

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

Ott

Fang

et al. 2021

Cancers

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Glioblastoma remains one of the deadliest and treatment-refractory human malignancies in large part due to its diffusely infiltrative nature, molecular heterogeneity, and capacity for immune escape. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes substantively to a wide variety of protumorigenic functions, including proliferation, anti-apoptosis, angiogenesis, stem cell maintenance, and immune suppression. We review the current state of knowledge regarding the biological role of JAK/STAT signaling in glioblastoma, therapeutic strategies, and future directions for the field.

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Section: Pharmaceutical Inhibition Of Stat3: Jak Inhibitorsmentioning

confidence: 99%

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

Ott

Fang

et al. 2021

Cancers

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“…Wei et al 31) reported the inhibitory effect of ruxolitinib on human medulloblastoma cells. In our previous study, we found that single-dose ruxolitinib (195 nM) inhibited glioma invasion via disruption of the IL-6 dependent JAK2/STAT3 pathway, and also significantly affected miR-20a and miR-17 expression 6) . Furthermore, Haile et al 11) demonstrated that ruxolitinib can cross the blood-brain barrier of mice.…”

Section: Discussionmentioning

confidence: 92%

“…Our pervious study demonstrated that ruxolitinib significantly inhibits the interleukin (IL)-6 receptor complex, which is dependent on the JAK2/STAT3 axis, at the gene expression level. Furthermore, microRNA-17 and microRNA-20a were found to be affected by ruxolitinib, and may be involved in the regulation of U87 glioma cell invasion 6) . In the present study, we investigated the possible effect of increasing doses of ruxolitinib on IFN-α and IFN-γ receptor downstream of JAK/ STAT signaling in human glioblastoma U87 tumor spheres, which is an in vitro model of tumor tissue 32) .…”

Section: Introductionmentioning

confidence: 98%

The Dose Dependent Effects of Ruxolitinib on the Invasion and Tumorigenesis in Gliomas Cells via Inhibition of Interferon Gamma-Depended JAK/STAT Signaling Pathway

Doğanlar

2020

J Korean Neurosurg Soc

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Objective : Glioblastoma multiforme (GBM) is the most aggressive for of brain tumor and treatment often fails due to the invasion of tumor cells into neighboring healthy brain tissues. Activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is essential for normal cellular function including angiogenesis, and has been proposed to have a pivotal role in glioma invasion. This study aimed to determine the dose-dependent effects of ruxolitinib, an inhibitor of JAK, on the interferon (IFN)-I/IFN-α/IFN-β receptor/STAT and IFN-γ/IFN-γ receptor/STAT1 axes of the IFN-receptor-dependent JAK/STAT signaling pathway in glioblastoma invasion and tumorigenesis in U87 glioblastoma tumor spheroids. Methods : We administered three different doses of ruxolitinib (50, 100, and 200 nM) to human U87 glioblastoma spheroids and analyzed the gene expression profiles of IFNs receptors from the JAK/STAT pathway. To evaluate activation of this pathway, we quantified the phosphorylation of JAK and STAT proteins using Western blotting. Results : Quantitative real-time polymerase chain reaction analysis demonstrated that ruxolitinib led to upregulated of the IFN-α and IFN-γ while no change on the hypoxia-inducible factor-1α and vascular endothelial growth factor expression levels. Additionally, we showed that ruxolitinib inhibited phosphorylation of JAK/STAT proteins. The inhibition of IFNs dependent JAK/STAT signaling by ruxolitinib leads to decreases of the U87 cells invasiveness and tumorigenesis. We demonstrate that ruxolitinib may inhibit glioma invasion and tumorigenesis through inhibition of the IFN-induced JAK/STAT signaling pathway. Conclusion : Collectively, our results revealed that ruxolitinib may have therapeutic potential in glioblastomas, possibly by JAK/ STAT signaling triggered by IFN-α and IFN-γ.

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“…Following our mixed-methods content analysis, the key role for hsa-miR-20a, hsa-miR-21 and hsa-miR-10a was revealed in the regulation of gene expression in GBM pathophysiology. The functional role of hsa-miR-20a, which is found overexpressed in GBM, based on its validated targets TIMP-2, TGFb-RII and CTGF, is associated with increased cell invasion, angiogenesis and cell growth [ 26 , 29 , 30 ]. The upregulation of hsa-miR-21 has been correlated with reduced cellular radiosensitivity and chemosensitivity, through its implication in DNA-repair mechanisms and cell-cycle linked pathways [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

A 3-miRNA Signature Enables Risk Stratification in Glioblastoma Multiforme Patients with Different Clinical Outcomes

et al. 2022

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Malignant gliomas constitute a complex disease phenotype that demands optimum decision-making as they are highly heterogeneous. Such inter-individual variability also renders optimum patient stratification extremely difficult. microRNA (hsa-miR-20a, hsa-miR-21, hsa-miR-21) expression levels were determined by RT-qPCR, upon FFPE tissue sample collection of glioblastoma multiforme patients (n = 37). In silico validation was then performed through discriminant analysis. Immunohistochemistry images from biopsy material were utilized by a hybrid deep learning system to further cross validate the distinctive capability of patient risk groups. Our standard-of-care treated patient cohort demonstrates no age- or sex- dependence. The expression values of the 3-miRNA signature between the low- (OS > 12 months) and high-risk (OS < 12 months) groups yield a p-value of <0.0001, enabling risk stratification. Risk stratification is validated by a. our random forest model that efficiently classifies (AUC = 97%) patients into two risk groups (low- vs. high-risk) by learning their 3-miRNA expression values, and b. our deep learning scheme, which recognizes those patterns that differentiate the images in question. Molecular-clinical correlations were drawn to classify low- (OS > 12 months) vs. high-risk (OS < 12 months) glioblastoma multiforme patients. Our 3-microRNA signature (hsa-miR-20a, hsa-miR-21, hsa-miR-10a) may further empower glioblastoma multiforme prognostic evaluation in clinical practice and enrich drug repurposing pipelines.

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Inhibition of the invasion of human glioblastoma u87 cell line by ruxolitinib: a molecular player of mir-17 and mir-20a regulating jak/stat pathway

Cited by 9 publications

References 0 publications

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

The Dose Dependent Effects of Ruxolitinib on the Invasion and Tumorigenesis in Gliomas Cells via Inhibition of Interferon Gamma-Depended JAK/STAT Signaling Pathway

A 3-miRNA Signature Enables Risk Stratification in Glioblastoma Multiforme Patients with Different Clinical Outcomes

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