Long Noncoding RNA WEE2-AS1 Plays an Oncogenic Role in Glioblastoma by Functioning as a Molecular Sponge for MicroRNA-520f-3p

The long noncoding RNA WEE2 antisense RNA 1 (WEE2-AS1) plays an oncogenic role in hepatocellular carcinoma and triple negative breast cancer progression. In this study, we investigated the expression and roles of WEE2-AS1 in glioblastoma (GBM). Furthermore, the molecular mechanisms behind the oncogenic actions of WEE2-AS1 in GBM cells were explored in detail. WEE2-AS1 expression was detected using quantitative real-time polymerase chain reaction. The roles of WEE2-AS1 in GBM cells were evaluated by the cell counting kit-8 assay, flow cytometric analysis, Transwell cell migration and invasion assays, and tumor xenograft experiments. WEE2-AS1 expression was evidently enhanced in GBM tissues and cell lines compared with their normal counterparts. An increased level of WEE2-AS1 was correlated with the average tumor diameter, Karnofsky Performance Scale score, and shorter overall survival among GBM patients. Functionally, depleted WEE2-AS1 attenuated GBM cell proliferation, migration, and invasion in vitro, promoted cell apoptosis, and impaired tumor growth in vivo. Mechanistically, WEE2-AS1 functioned as a molecular sponge for microRNA- 520f-3p (miR-520f-3p) and consequently increased specificity protein 1 (SP1) expression in GBM cells. A series of recovery experiments revealed that the inhibition of miR-520f-3p and upregulation of SP1 could partially abrogate the influences of WEE2-AS1 downregulation on GBM cells. In conclusion, WEE2-AS1 can adsorb miR-520f-3p to increase endogenous SP1 expression, thereby facilitating the malignancy of GBM. Therefore, targeting the WEE2-AS1–miR-520f-3p–SP1 pathway might be a promising therapy for the management of GBM in the future.     

Patterns of management and outcomes of unifocal versus multifocal glioblastoma

BackgroundGlioblastoma (GBM) presents as a solitary lesion (unifocal), or as multiple discrete lesions (multifocal). Multifocal GBM may have a worse prognosis as compared to unifocal GBM, but existing data are limited to small institutional series. The purpose of the present study was to evaluate demographic and clinical characteristics of patients with unifocal versus multifocal GBM to highlight demographic differences and clinical outcomes for two groups of patients.MethodsThe National Cancer Database (NCDB) was queried (2004–2016) for patients newly diagnosed with either unifocal or multifocal GBM. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling.ResultsOf 45,268 total patients, 37,483 (82.8%) had unifocal GBM and 7,785 (17.2%) had multifocal GBM. Patients with unifocal GBM more frequently received gross total resection (GTR) (41.2% versus 25.8%, p < 0.001) and conventionally fractionated radiation therapy (RT) (48.2% versus 42.7%, p < 0.001). Patients with multifocal GBM had a higher rate of surgery with biopsy only (34.0% compared to 24.1%, p < 0.001). Median OS was 12.8 months versus 8.3 months (p < 0.001) for patients with unifocal GBM or multifocal GBM, respectively. On multivariate analysis, factors associated with improved OS included unifocal disease, MGMT methylation, RT use, and chemotherapy use.ConclusionsThis is the largest study to date describing outcomes for patients with multifocal GBM, and it shows that multifocal GBM is associated with a decreased use both of GTR and conventionally fractionated RT, as well as worse median OS. Further research is needed to improve clinical outcomes for patients with multifocal GBM.     

Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

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Targeting Aurora kinase B attenuates chemoresistance in glioblastoma via a synergistic manner with temozolomide

BackgroundRecent studies have demonstrated that aberrant expression or activation of kinases results in oncogenesis of a wide range of cancers including GBM. Inhibition of kinases expression induces a reduction of therapy resistance. In this study, we investigate the underlying mechanism by which glioblastoma (GBM) cells acquire resistance to Temozolomide (TMZ) through Aurora kinase B (AURKB) thus to identify novel therapeutic targets and prognostic biomarkers for GBM.MethodsAURKB was identified as a key candidate kinase-encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of AURKB in oncogenesis and chemoresistance were investigated by lentivirus-dependent silencing of AURKB combined with qRT-PCR, western blot and in vivo intra-cranial xenograft mice models. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. Lastly, Chou-Talalay method was used to confirm the synergistic effect of TMZ combined with AURKB inhibitor.ResultsAURKB was among the most significantly up-regulated kinase-coding genes in TMZ resistant GBM cells according to database GSE68029, moreover, an increased expression of AURKB was closely associated with poor prognosis in glioma and GBM patients. AURKB knock-down resensitized U87 resistant cells to TMZ both in vitro and in vivo. Additionally, the combination of TMZ and Hesperadin, a specific AURKB inhibitor, significantly suppressed the proliferation of TMZ resistant GBM cells thus dramatically prolonged the survival of xenograft mice viaa synergistic effect with TMZ.ConclusionElevated AURKB expression was strongly correlated to TMZ resistant acquisition and poor prognosis, furthermore, targeting AURKB would be a potential therapeutic target for GBM patients.     

A new der(1;7)(q10;p10) leading to a singular 1p loss in a case of glioblastoma with oligodendroglioma component

The combined 1p‐/19q‐ deletions in oligodendrogliomas originate from translocation between both chromosomes. In the few cases of oligoastrocytomas and glioblastomas with an oligodendroglioma component (GBMO) where only 1p deletion was described, the origin remains unknown. We report the first case of GBMO, in which a single 1p deletion was detected and was linked to a translocation between chromosomes 1 and 7. Fresh surgical specimens were collected during surgery and the samples were used for cell culture, touch preparation smear slides (TP slides) and DNA extraction. Peripheral venous blood was also collected from the patient. G‐banding using Trypsin and stained with Giemsa (GTG) banding and karyotyping were performed and 1p‐/19q‐, TP53, PTEN and c‐MYC were analyzed by fluorescent in situ hybridization (FISH). Multicolor FISH (mFISH) and microsatellites analyses were also performed to complete the investigation. Three‐dimensional quantitative FISH (3D‐QFISH) of telomeres was performed on nuclei from TP slides and analyzed using TeloView^TM to determine whether the 3D telomere profile as an assessment of telomere dysfunction and a characterization of genomic instability could predict the disease aggressiveness. An unbalanced chromosomal translocation was found in all metaphases and confirmed by mFISH. The karyotype of the case is: 50～99,XXX, +der(1;7)(q10;p10),inc[47] The derivative chromosome was found in all 47 analyzed cells, but the number of derivatives varied from one to four. There was neither imbalance in copy number for genes TP53 and PTEN, nor amplification of c‐MYC gene. We did not find loss of heterozygosity with analysis of microsatellite markers for chromosomes 1p and 19q in tumor cells. The 3D‐telomere profile predicted a very poor prognostic and short‐term survival of the patient and highlights the potential clinical power of telomere signatures as a solid biomarker of GBMO. Furthermore, this translocation between chromosomes 1 and 7 led to a singular 1p deletion in this GBMO and may generate the 1p and 7q deletions.     

Alteration of Connexin43 expression in a rat model of obesity-related glomerulopathy

It is accepted that alteration of connexin43 (Cx43) expression in glomeruli is a common pathological response in several forms of kidney diseases. To date, however the change of the Cx43 expression in obesity-related glomerulopathy (ORG) has not been reported. In this study, the alteration of Cx43 expression in the glomeruli of rat with ORG was defined. Five-week-old rats were fed with high-fat diet for 18 weeks to establish the ORG model, then the histological change of glomeruli, the foot process effacement of podocyte, the markers for podocyte injury (nephrin,podocin and WT1) and Cx43 expression in glomeruli were examined respectively. The results demonstrated metabolic disorder, hyperinsulinemia, systemic inflammation and microalbuminuria in ORG rats. There was significant hypertrophy, glomerular expansion and inflammatory cell infiltration in the kidney of ORG rats compared to the control group. Significant foot process effacement of the podocyte in the glomeruli, nephrin loss and density reduction were shown in the ORG rats, and Cx43 expression was significant upregulated in glomeruli of ORG rats compared to the control group. The results indicate the correlation of overexpressed Cx43 with the obesity related renal inflammation and suggest that Cx43 might be a potential target in the development of obesity related glomerulopathy.