Fos-related antigen-1 (Fra-1) is a regulator of glioma cell malignant phenotype

Kesari, Santosh; Bota, Daniela

doi:10.4161/cbt.11.3.14718

Cited by 7 publications

(7 citation statements)

References 34 publications

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“…Hence, the gene regulatory networks proposed by our computational analysis suggest a novel molecular mechanism associated with GBM survival in which FRA-1 acts as a transcription regulator of IGFBP2. The study of Kesari and Bota (2011) confirmed our hypothesis that IGFBP2 can enhance GBM invasion via TF AP1 (FOS-JUN). Metalloproteinases like MMP-2/MMP-9 have been reported earlier to be regulated by FRA-1 in several cancers including GBM ( Debinski and Gibo, 2005 ; Adiseshaiah et al, 2008 ; Kimura et al, 2011 ; Prywes and Henckels, 2013 ).…”

Section: Discussionsupporting

confidence: 76%

“…The TFs NANOG and REST are critical for self-renewal and maintenance of oncogenic signatures in glioblastoma stem-like cells ( Kamal et al, 2012 ; Bradshaw et al, 2016 ); PPARG has emerged as a promising therapeutic target as its agonists increased median survival in GBM patients ( Ellis and Kurian, 2014 ); NF-κB is implicated in several processes like invasion, epithelial–mesenchymal transition ( Yamini, 2018 ), resistance to radiotherapy ( Avci et al, 2020 ), and maintenance of cancer stem-like cells ( da Hora et al, 2019 ); and FRA-1/FOSL1 has been reported to be important in maintenance/progression of malignant glioma ( Debinski and Gibo, 2005 ). FRA-1 along with JUN-B modulates a malignant feature of GBM by regulating the expression of the metalloproteinases like MMP-2 and MMP-9 ( Kesari and Bota, 2011 ). Among these 12 TFs, we found that FRA-1 has a significant impact upon survival and has a higher expression in STS.…”

Section: Discussionmentioning

confidence: 99%

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IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

et al. 2021

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Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

et al. 2021

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“…Overexpression of FOSL1 may cause carcinogenesis, and is a typical characteristic of glioma [63]. FOSL1 over-expression induced differentiation, inhibited proliferation, growth and reduced tumorogenicity of C6 glioma cell line, so it may be a potential target for glioma treatment [64].…”

Section: Discussionmentioning

confidence: 99%

Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: cellular, biochemical and gene expression analysis

Antal

Hackler²,

Shen

et al. 2014

Lipids Health Dis

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BackgroundBased on previous observations a potential resort in the therapy of the particularly radioresistant glioma would be its treatment with unsaturated fatty acids (UFAs) combined with irradiation.MethodsWe evaluated the effect of different UFAs (arachidonic acid (AA), docosahexaenoic acid (DHA), gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and oleic acid (OA)) on human U87 MG glioma cell line by classical biochemical end-point assays, impedance-based, real-time cellular and holographic microscopic analysis. We further analyzed AA, DHA, and GLA at morphological, gene and miRNA expression level.ResultsCorresponding to LDH-, MTS assays and real-time cytoxicity profiles AA, DHA, and GLA enhanced the radio sensitivity of glioma cells. The collective application of polyunsaturated fatty acids (PUFAs) and irradiation significantly changed the expression of EGR1, TNF-α, NOTCH1, c-MYC, TP53, HMOX1, AKR1C1, NQO1, while up-regulation of GADD45A, EGR1, GRP78, DDIT3, c-MYC, FOSL1 were recorded both in response to PUFA treatment or irradiation alone. Among the analyzed miRNAs miR-146 and miR-181a were induced by DHA treatment. Overexpression of miR-146 was also detected by combined treatment of GLA and irradiation.ConclusionsBecause PUFAs increased the radio responsiveness of glioma cells as assessed by biochemical and cellular assays, they might increase the therapeutic efficacy of radiation in treatment of gliomas. We demonstrated that treatment with DHA, AA and GLA as adjunct to irradiation up-regulated the expression of oxidative-stress and endoplasmic reticulum stress related genes, and affected NOTCH1 expression, which could explain their additive effects.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-511X-13-142) contains supplementary material, which is available to authorized users.

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“…16 Actually, Fra-1 has been considered to have prognostic significance, particularly for human esophageal squamous cell carcinoma, and to be a regulator of the malignant phenotype of glioma cells. 17,18 We previously reported that Fra-1 has a key role in the polarization of TAMs from the M1 to the M2 phenotype. In other words, expression of Fra-1 could be upregulated in TAMs that responded to stimulation by TME, leading to an increased proportion of M2like TAMs.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene

et al. 2013

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One of the hallmarks of malignancy is the polarization of tumor-associated macrophages (TAMs) from a pro-immune (M1-like) phenotype to an immune-suppressive (M2-like) phenotype. However, the molecular basis of the process is still unclear. MicroRNA (miRNA) comprises a group of small, non-coding RNAs that are broadly expressed by a variety of organisms and are involved in cell behaviors such as suppression or promotion of tumorigenesis. Here, we demonstrate that miR-19a-3p, broadly conserved among vertebrates, was downregulated in RAW264.7 macrophage cells of the M2 phenotype in conditoned medium of 4T1 mouse breast tumor cells. This downregulation correlated with an increased expression of the Fra-1 gene, which was reported to act as a pro-oncogene by supporting the invasion and progression of breast tumors. We found significant upregulation of miR-19a-3p in RAW264.7 macrophages after transfection with a miR-19a-3p mimic that resulted in a significant suppression of the expression of this gene. In addition, we could measure the activity of binding between miR-19a-3p and Fra-1 with a psiCHECK luciferase reporter system. Further, transfection of RAW264.7 macrophage cells with the miR-19a-3p mimic decreased the expression of the Fra-1 downstream genes VEGF, STAT3 and pSTAT3. Most importantly, the capacity of 4T1 breast tumor cells to migrate and invade was impaired in vivo by the intratumoral injection of miR-19a-3p. Taken together, these findings indicate that miR-19a-3p is capable of downregulating the M2 phenotype in M2 macrophages and that the low expression of this miRNA has an important role in the upregulation of Fra-1 expression and induction of M2 macrophage polarization.

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Fos-related antigen-1 (Fra-1) is a regulator of glioma cell malignant phenotype

Cited by 7 publications

References 34 publications

IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: cellular, biochemical and gene expression analysis

MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene

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