Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genetic variations in AURORA cell cycle kinases are associated with glioblastoma multiforme.

ABSTRACT: Glioblastoma multiforme (GBM) is the most frequent type of primary astrocytomas. We examined the association between single nucleotide polymorphisms (SNPs) in Aurora kinase A (AURKA), Aurora kinase B (AURKB), Aurora kinase C (AURKC) and Polo-like kinase 1 (PLK1) mitotic checkpoint genes and GBM risk by qPCR genotyping. In silico analysis was performed to evaluate effects of polymorphic biological sequences on protein binding motifs. Chi-square and Fisher statistics revealed a significant difference in genotypes frequencies between GBM patients and controls for AURKB rs2289590 variant (p = 0.038). Association with decreased GBM risk was demonstrated for AURKB rs2289590 AC genotype (OR = 0.54; 95% CI = 0.33-0.88; p = 0.015). Furthermore, AURKC rs11084490 CG genotype was associated with lower GBM risk (OR = 0.57; 95% CI = 0.34-0.95; p = 0.031). Bioinformatic analysis of rs2289590 polymorphic region identified additional binding site for the Yin-Yang 1 (YY1) transcription factor in the presence of C allele. Our results indicated that rs2289590 in AURKB and rs11084490 in AURKC were associated with a reduced GBM risk. The present study was performed on a less numerous but ethnically homogeneous population. Hence, future investigations in larger and multiethnic groups are needed to strengthen these results.

SUBMITTER: Mesic A

PROVIDER: S-EPMC8408269 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme.

Project description:Chromosomal abnormalities and genomic instability are common features of, and possible driving forces in, tumorigenesis. Recently, several mitotic proteins that are critical to proper chromosome segregation have been identified. Members of the Aurora kinase family have been identified as having important roles in mitosis; overexpression induces multicellularity and fosters polyploidy. As aneuploidy is a common feature of malignant gliomas, particularly glioblastomas (GBMs), we examined 25 prospectively collected GBMs to assess the role that overexpression of one member of this family, Aurora B, might have in the clinical behaviour of GBMs. Aurora B expression levels were markedly correlated with a shortened survival. Aurora B expression was not directly related to age, tumour proliferation status or to several common molecular changes found in GBMs. These results suggest that Aurora B may be a prognostic feature of impaired survival and a novel therapeutic target in some patients.

| S-EPMC1860618 | biostudies-literature

Silencing of the nucleocytoplasmic shuttling protein karyopherin a2 promotes cell-cycle arrest and apoptosis in glioblastoma multiforme.

Project description:We have previously shown that the nucleocytoplasmic carrier karyopherin a2 (KPNA2) is overexpressed in glioblastoma multiforme (GBM) whereas its expression is inversely associated with patient prognosis. However, the promoting role of KPNA2 in gliomagenesis is still poorly understood. This study aims to further elucidate this role of KPNA2 in in vitro GBM models. From four different tested GBM cell lines, the U87MG showed the highest proliferation, low adherence and outgrowth in 3D clusters as well as the highest expression of KPNA2, all features conferring greater malignant behaviour. Silencing of KPNA2 via siRNA interference in those cells significantly decreased their proliferative capacity (p = 0.001). We further observed both a significant cell cycle phase arrest (p = 0.040) and the promoting of cellular apoptosis (p = 0.016) as well as a strong trend (p = 0.062) for an inhibition of nuclear import of c-Myc. This study confirms that a higher expression of KPNA2 in GBM is associated with a more malignant phenotype also in in vitro models. While increased expression of KPNA2 promotes proliferation and survival of GBM tumour cells, silencing of KPNA2 conferred a less malignant behaviour. Our results strongly suggest that silencing of KPNA2 may play an important role in modulation of malignant features of GBM cells.

| S-EPMC6173355 | biostudies-literature

Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol Through the Modulation of EGFR and CSC Signaling Pathways.

Project description:Cancer stem cells (CSCs), a small subpopulation of cells existing in the tumor microenvironment promoting cell proliferation and growth. Targeting the stemness of the CSC population would offer a vital therapeutic opportunity. 3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), a small synthetic phenol compound, is proposed to play a significant role in controlling the CSC proliferation and survival. We assessed the potential therapeutic effects of THTMP on glioblastoma multiforme (GBM) and its underlying mechanism in various signaling pathways. To fully comprehend the effect of THTMP on the CSCs, CD133+ GBM stem cell (GSC) and CD133- GBM Non-stem cancer cells (NSCC) population from LN229 and SNB19 cell lines was used. Cell cycle arrest, apoptosis assay and transcriptome analysis were performed for individual cell population. THTMP strongly inhibited NSCC and in a subtle way for GSC in a time-dependent manner and inhibit the resistance variants better than that of temozolomide (TMZ). THTMP arrest the CSC cell population at both G1/S and G2/M phase and induce ROS-mediated apoptosis. Gene expression profiling characterize THTMP as an inhibitor of the p53 signaling pathway causing DNA damage and cell cycle arrest in CSC population. We show that the THTMP majorly affects the EGFR and CSC signaling pathways. Specifically, modulation of key genes involved in Wnt, Notch and Hedgehog, revealed the significant role of THTMP in disrupting the CSCs' stemness and functions. Moreover, THTMP inhibited cell growth, proliferation and metastasis of multiple mesenchymal patient-tissue derived GBM-cell lines. THTMP arrests GBM stem cell cycle through the modulation of EGFR and CSC signaling pathways.

| S-EPMC7140667 | biostudies-literature

Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility.

Project description:Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk.The study is based on the largest series of PBT cases to date. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was genotyped for 68 SNPs. Data were analyzed using unconditional logistic regression.The results showed EGFRrs730437 and EGFRrs11506105 may decrease susceptibility to PBTs, whereas ERCC1rs3212986 may increase risk of these tumors. Moreover, stratified analyses indicated CHAF1Ars243341, CHAF1Ars2992, and XRCC1rs25487 were associated with a decreased risk of astrocytoma subtype. Furthermore, an increased risk of non-astrocytoma subtype associated with EGFRrs9642393, EME1rs12450550, ATMrs170548, and GLTSCRrs1035938 as well as a decreased risk of this subtype associated with XRCC4rs7721416 and XRCC4rs2662242 were detected.This study indicates SNPs in EGFR, ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4 may be associated with the risk of PBTs. Therefore, cell cycle and DNA repair pathways variations associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting pediatric and adult brain tumors might share similar etiological pathways.

| S-EPMC5325391 | biostudies-literature

Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation.

Project description:Next generation sequencing has become a powerful tool in dissecting and identifying mutations and genomic structural variants that accompany tumourigenesis. Sequence analysis of glioblastoma multiforme (GBM) illustrates the ability to rapidly identify mutations that may affect phenotype. Approximately 50% of human GBMs overexpress epidermal growth factor receptor (EGFR) which renders the EGFR protein a compelling therapeutic target. In brain tumours, attempts to target EGFR as a cancer therapeutic, however, have achieved little or no benefit. The mechanisms that drive therapeutic resistance to EGFR inhibitors in brain tumours are not well defined, and drug resistance contributes to the deadly and aggressive nature of the disease. Whole genome sequencing of four primary GBMs revealed multiple pathways by which EGFR protein abundance becomes deregulated in these tumours and will guide the development of new strategies for treating EGFR overexpressing tumours. Each of the four tumours displayed a different mechanism leading to increased EGFR protein levels. One mechanism is mediated by gene amplification and tandem duplication of the kinase domain. A second involves an intragenic deletion that generates a constitutively active form of the protein. A third combines the loss of a gene which encodes a protein that regulates EGFR abundance as well as an miRNA that modulates EGFR expression. A fourth mechanism entails loss of an ubiquitin ligase docking site in the C-terminal part of the protein whose absence inhibits turnover of the receptor.

| S-EPMC4432462 | biostudies-literature

BMI1 sustains human glioblastoma multiforme stem cell renewal.

Project description:Glioblastoma multiforme (GBM) is one of the most common and aggressive types of brain tumors. In GBM, a subpopulation of CD133-positive cancer initiating cells displays stem cell characteristics. The Polycomb group (PcG) and oncogene BMI1 is part of the Polycomb repressive complex 1 (PRC1) that regulates gene expression by modifying chromatin organization. Here we show that BMI1 is expressed in human GBM tumors and highly enriched in CD133-positive cells. Stable BMI1 knockdown using short hairpin RNA-expressing lentiviruses resulted in inhibition of clonogenic potential in vitro and of brain tumor formation in vivo. Cell biology studies support the notion that BMI1 prevents CD133-positive cell apoptosis and/or differentiation into neurons and astrocytes, depending on the cellular context. Gene expression analyses suggest that BMI1 represses alternate tumor suppressor pathways that attempt to compensate for INK4A/ARF/P53 deletion and PI(3)K/AKT hyperactivity. Inhibition of EZH2, the main component of the PRC2, also impaired GBM tumor growth. Our results reveal that PcG proteins are involved in GBM tumor growth and required to sustain cancer initiating stem cell renewal.

| S-EPMC6665439 | biostudies-literature

Znf179 induces differentiation and growth arrest of human primary glioblastoma multiforme in a p53-dependent cell cycle pathway.

Project description:Malignant glioblastoma multiforme (GBM) is an aggressive brain tumor with strong local invasive growth and a poor prognosis. One probable way to manipulate GBM cells toward a less invasive status is to reprogram the most malignant GBM cells to a more differentiated and less oncogenic phenotype. Herein, we identified a novel role of a RING finger protein Znf179 in gliomagenesis. Znf179 overexpression induced differentiation of primary GBM cells, which were accompanied with elevated glial fibrillary acidic protein (GFAP) expression through up-regulating several cell-cycle-related factors, p53, p21, and p27, and allowed the cell-cycle arrest in the G0/G1 phase. In addition, Znf179 was highly correlated with the prognosis and survival rates of glioma patients. The expression levels of Znf179 was relatively lower in glioma patients compared to normal people, and glioma patients with lower expression levels of Znf179 mRNA had poorer prognosis and lower survival rates. In conclusion, we provide novel insight that Znf179 can reprogram GBM cells into a more-differentiated phenotype and prevent the progression of gliomas to a more-malignant state through p53-mediated cell-cycle signaling pathways. Understanding the molecular mechanism of Znf179 in gliomagenesis could help predict prognostic consequences, and targeting Znf179 could be a potential biomarker for glioma progression.

| S-EPMC5500472 | biostudies-literature

Genetic diversity of propagating/stem cells in glioblastoma multiforme (GBM)

Project description:Glioblastoma multiforme (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intra-clonal genetic and phenotypic diversity and therapeutic resistance of cancer stem cells (CSCs). This interpretation embodies an implicit assumption that CSCs are themselves genetically diverse. To test this, we screened neurosphere cultures by SNP arrays to identify copy number alterations (CNA) (minimum of three) that could be visualised in single cells by multi-colour FISH. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in Nod/Scid mice allowed us to infer clonal phylogenic architecture and the likely derivation of functional CSCs. This proof-of-principle experiment revealed that more than one sub-clone (but not all) in each GBM had functionally defined, genetically distinct stem cells.

2015-01-22 | GSE45185 | GEO

Polymorphisms associated with asthma are inversely related to glioblastoma multiforme.

Project description:A reduced risk of primary malignant adult brain tumors is observed among people reporting asthma, hay fever, and other allergic conditions; however, findings may be attributed to prediagnostic effects of tumors or recall bias. To determine whether asthma and allergic condition polymorphisms are inversely related to glioblastoma multiforme (GBM) risk, we conducted a population-based case-control study of 111 GBM patients and 422 controls. We identified five single nucleotide polymorphisms on three genes previously associated with asthma [interleukin (IL)-4RA, IL-13, ADAM33] and one gene associated with inflammation (cyclooxygenase-2). Confirming previous literature, we found that self-reported asthma, eczema, and fever are inversely related to GBM [e.g., asthma odds ratio (OR), 0.64; 95% confidence interval (CI), 0.33-1.25]. In addition, IL-4RA Ser478Pro TC, CC, and IL-4RA Gln551Arg AG, AA are positively associated with GBM (OR, 1.64; 95% CI, 1.05-2.55; 1.61; 95% CI, 1.05-2.47), whereas IL-13 -1,112 CT, TT is negatively associated with GBM (0.56; 95% CI, 0.33-0.96). Each of these polymorphism-GBM associations is in the opposite direction of a corresponding polymorphism-asthma association, consistent with previous findings that self-reported asthmatics and people with allergic conditions are less likely to have GBM than are people who do not report these conditions. Because we used germ line polymorphisms as biomarkers of susceptibility to asthma and allergic conditions, our results cannot be attributed to recall bias or effects of GBM on the immune system. However, our findings are also consistent with associations between IL-4RA, IL-13, and GBM that are independent of their role in allergic conditions.

| S-EPMC1762912 | biostudies-literature

Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.

Project description:Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G(1) cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy.

| S-EPMC2855904 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data