STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma

Thota, Balaram; Arivazhagan, Arimappamagan; Thennarasu, Kandavel; Shastry, Arun; Pandey, Paritosh; Chandramouli, Bangalore A.; Hegde, Anupama; Kondaiah, Paturu; Santosh, Vani

doi:10.3171/2014.4.jns131198

Cited by 32 publications

(24 citation statements)

References 51 publications

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“…7,18 A previous study showed that IGFBP3 knockdown impaired the proliferation capability of U-251 MG glioma cells in vitro. 24 Here, we performed IGFBP3 knockdown by expressing IGFBP3 siRNAs in five glioma cell lines and four GBM primary cell lines and confirmed a growth-suppressing effect of IGFBP3 depletion in vitro; we further suggested a tumor-growth suppression effect of IGFBP3 siRNAs in in vivo intracranial xenograft mouse models. Our findings demonstrate that depleting IGFBP3 expression by IGFBP3 siRNA is a novel and promising targeted therapy in treating GBM patients.…”

Section: Discussionsupporting

confidence: 60%

Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma

Chen

Lin

et al. 2020

Journal of Neurosurgery

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OBJECTIVEDespite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment.METHODSIGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models.RESULTSWe demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice.CONCLUSIONSOur findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.

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Section: Discussionsupporting

confidence: 60%

Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma

Chen

Lin

et al. 2020

Journal of Neurosurgery

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“…Finally, the DNA/protein transcription factor interaction array experiment revealed that HEY1 binds a large number of transcription factors, including both STAT1 and STAT4. Although PCR data does not show si-HEY1 to have a significant effect on STAT1, previous research indicates the overexpression of STAT1 is unique to glioblastoma samples when compared to normal brain tissue samples [ 26 ]. More significantly, STAT1 levels have been correlated with shorter median survival time in patients with GBM (STAT1+ = 13 months; STAT1- = 21 months) [31].…”

Section: Discussionmentioning

confidence: 99%

Methylation regulates HEY1 expression in glioblastoma

et al. 2017

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Glioblastoma (GBM) remains one of the most lethal and difficult-to-treat cancers of the central nervous system. The poor prognosis in GBM patients is due in part to its resistance to available treatments, which calls for identifying novel molecular therapeutic targets. In this study, we identified a mediator of Notch signaling, HEY1, whose methylation status contributes to the pathogenesis of GBM. Datamining studies, immunohistochemistry and immunoblot analysis showed that HEY1 is highly expressed in GBM patient specimens. Since methylation status of HEY1 may control its expression, we conducted bisulphite sequencing on patient samples and found that the HEY1 promoter region was hypermethylated in normal brain when compared to GBM specimens. Treatment on 4910 and 5310 xenograft cell lines with sodium butyrate (NaB) significantly decreased HEY1 expression with a concomitant increase in DNMT1 expression, confirming that promoter methylation may regulate HEY1 expression in GBM. NaB treatment also induced apoptosis of GBM cells as measured by flow cytometric analysis. Further, silencing of HEY1 reduced invasion, migration and proliferation in 4910 and 5310 cells. Furthermore, immunoblot and q-PCR analysis showed the existence of a potential positive regulatory loop between HEY1 and p53. Additionally, transcription factor interaction array with HEY1 recombinant protein predicted a correlation with p53 and provided various bonafide targets of HEY1. Collectively, these studies suggest HEY1 may be an important predictive marker for GBM and potential target for future GBM therapy.

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“…These data indicate that Pyk2 has a key role in the basic migratory activity of U87 and HS683, but not A172, GL261, and C6 cells. These might suggest that in addition to Pyk2 other pathways may be involved in the regulation of basal rates of migration in gliomas such as Insulin-like growth factor binding protein 3 (IGFBP-3) that has been implicated in the pathogenesis of gliomas and was shown to be involved in proliferation and the invasive capacity of glioma cells [ 53 ]. Other studies demonstrated that Culllin1 (Cul1) is increased significantly in malignant brain tumors, and that silencing of Cul1 in glioma cells inhibited the cell migration and invasion abilities as well as down-regulated MMP-2 and MMP-9 expression that also greatly contribute to the reduced cell invasion and migration abilities [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway

et al. 2015

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Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells.

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STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma

Cited by 32 publications

References 51 publications

Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma

Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma

Methylation regulates HEY1 expression in glioblastoma

Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway

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