Survival Of Glioma Patients Research Articles

Comprehensive Analysis of REST/NRSF Gene in Glioma and Its ceRNA Network Identification.

We sought to clarify the clinical relationship between REST/NRSF expression and the prognosis of glioma and explore the REST-associated competitive endogenous RNA (ceRNA) network in glioma. We downloaded RNA-seq, miRNA-seq and correlated clinical data of 670 glioma patients from The Cancer Genome Atlas and analyzed the correlation between REST expression, clinical characteristics and prognosis. Differentially expressed genes (DEGs) were identified with DESeq2 and analyzed with Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) using the Profiler package. Starbase was used to explore the regulatory interaction between REST and miRNAs or LncRNAs. The lncRNA-miRNA-REST ceRNA network was constructed with Cytoscape. RT-qPCR, WB, CCK8, wound-healing, and luciferase assays were performed to validate the ceRNA network. Results showed that REST expression was significantly higher in glioma patients than normal samples. Higher REST expression was significantly associated with worse overall survival, progression-free interval, and worse disease-specific survival in glioma patients. The DEGs of mRNA, miRNA, and lncRNA were identified, and GO and KEGG enrichment analyses were performed. Finally, REST-associated ceRNA networks, including NR2F2-AS1-miR129-REST and HOTAIRM1-miR137-REST, were experimentally validated. Thus, REST may be a prognostic biomarker and therapeutic target in glioma, and its regulatory network validated in this study may provide insights into glioma's molecular regulatory mechanisms.

FXYD2 mRNA expression represents a new independent factor that affects survival of glioma patients and predicts chemosensitivity of patients to temozolomide

PurposeGlioma is the most common primary intracranial tumor. Owing to the poor prognosis associated with high-grade gliomas, there is an urgent need to identify biomarkers related to prognosis and treatment sensitivity. Here, we analyze the expression of FXYD2 mRNA in gliomas, and explore its clinical prognostic value and significance in this disease.MethodsClinical features, FXYD2 mRNA expression levels, and survival data were analyzed for 516 glioma patients from the Chinese Glioma Genome Map Project, 481 from the cancer genome map datbase and 268 from the molecular braintumor database. The expression patterns for FXYD2 mRNA were compared using the chi-square test, and overall survival (OS) of glioma patients was evaluated according to FXYD2 mRNA expression levels. The factors affecting glioma survival were evaluated by Cox univariate and multivariate regression analysis.ResultsFXYD2 mRNA expression was related to the grade of gliomas. The higher the level, the lower the expression. Meanwhile related to the pathological classification of gliomas. Oligodendroglioma, IDH-mutant and 1p/19q-codeleted was higher than Astrocytoma, IDH-mutant, higher than Glioblastoma, IDH-wildtype. Moreover, temozolomide (TMZ) chemotherapy was found to be an independent factor affecting survival in patients with high FXYD2 mRNA expression, but not in patients with low expression.ConclusionFXYD2 mRNA expression represents a new independent factor affecting the survival of glioma patients and may serve as an independent prognostic indicator to predict the sensitivity of gliomas to TMZ.

Nuclear FABP7 regulates cell proliferation of wild-type IDH1 glioma through caveolae formation.

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild‐type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular‐targeted therapies is of paramount importance. Fatty acid‐binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild‐type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin‐1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin‐1 promoter through controlling the nuclear acetyl‐CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7. Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin‐1 expression, increased levels of histone acetylation, and increased levels of acetyl‐CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin‐1, and this mechanism is critically important for IDH1wt tumor biology.

Curcumol inhibits malignant biological behaviors and TMZ-resistance in glioma cells by inhibiting long noncoding RNA FOXD2-As1-promoted EZH2 activation.

Currently, conventional treatment is not sufficient to improve the survival of glioma patients. Hence, adopting novel personalized treatment programs is imperative. Curcumol, a Chinese herbal medicine extract from the roots of Rhizoma Curcumae, has attracted significant interest due to its beneficial pharmacological activities. The current study revealed that curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance in glioma cells in vitro and in vivo. Next, the potential molecular mechanisms of curcumol in inhibiting glioma were investigated. We found that the long non-coding RNA (lncRNA) FOXD2-As1 might contribute to the effects of curcumol on glioma cells. Enforced expression of FOXD2-As1 attenuated the curcumol-induced reduction in glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-As1 reversed the inhibitory effect of curcumol on the binding ability of EZH2 and H3K27me3 modification in the promoter regions of anti-oncogenes. Our results showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-As1-mediated EZH2 activation. Our study offers the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis

In human gliomas, anti-tumor T cell responses are inhibited through induction of local and systemic immunosuppression. Immune checkpoint blockade is proving to be a success in several types of cancers. However, many studies reported that the treatment of glioblastoma patients with anti-CTLA-4 or anti-PD-1 has no survival benefit compared to standard chemotherapy. This study aimed to investigate the expression and role of VISTA, a newly described immune checkpoint regulator, in human gliomas. mRNA expression was assessed in a total of 87 samples from glioma patients. 57 glioma tissues were taken at different grades. 20 peripheral blood mononuclear cells (PBMC) samples were taken before surgery and ten after surgery, all from the same set of patients. As for the control, ten specimens of PBMC were taken from healthy donors. Protein expression using immunohistochemistry was performed for 30 patients. The Cancer Genome Atlas (TCGA) data set, was also used to investigate VISTA expression through analysis of RNA-seq data of 667 glioma patients. In the Moroccan cohort, VISTA gene expression was significantly upregulated in glioma tissues related to PBMC of healthy donors. This high expression was specific to patient tissues since VISTA expression in PBMC was low when assessed either before or after surgery. Besides, VISTA exhibited higher expression levels in grade III/IV relative to grade I/II glioma patients. Interestingly, VISTA correlated positively with PD-1 expression. PD-1 also showed elevated expressions in higher glioma grades. The TCGA cohort corroborated these observations. Indeed, VISTA was also found to be strongly expressed in high grades. It was positively correlated with other critical immune checkpoints. Finally, increased VISTA transcript levels were associated with weak overall survival of glioma patients. Our study highlighted a correlation between high levels of VISTA expression and poor prognosis in glioma patients. VISTA might be involved in glioma progression and could be considered as a possible new therapeutic target, especially in advanced gliomas.

The persistence of seizures after tumor resection negatively affects survival in low-grade glioma patients: a clinical retrospective study.

Seizures are the most common clinical manifestation of low-grade glioma (LGG). Many papers hypothesized an influence of epilepsy on glioma progression. To our knowledge, no clinical study demonstrated a direct relationship between persistence of epileptic seizures after surgery and overall survival (OS) in LGG patients. The present study aims at investigating the correlation between post-operative seizure outcome and survival in tumor-related epilepsy (TRE) patients. We performed a retrospective analysis of adult patients affected by TRE who underwent surgery for resection of LGG in a single high-volume neurosurgical center. Seizure outcome was assessed 1year after surgery and categorized according to Engel classification. Clinical, molecular and radiological features were evaluated in univariate and multivariate analyses to investigate the correlation with OS. A total of 146 patients met the inclusion criteria. Histopathological diagnosis was Diffuse Astrocytoma isocitrate dehydrogenase (IDH) wild type in 16 patients (11%), Diffuse astrocytoma IDH mutated in 89 patients (61%) and oligodendroglioma IDH mutated, 1p 19q codeleted in 41 patients (28%). 1year after surgery, 103 (70.6%) patients were in Engel class 1. Median duration of follow-up period was 69.5months. Median OS was 79.3 (72.2-86.4) months in the whole population, while it was 86.8 (78.4-95.2), 63.9 (45.7-82), 63.7 (45.2-82.2) and 47.5 (18.3-76.6) months for patients in Engel class 1, 2, 3 and 4, respectively. In a univariate analysis, Engel class evaluated 1year after surgery significantly influenced OS (p < 0.01). Multivariate analysis showed that OS was independently associated with extent of resection (p = 0.02), molecular class (p < 0.01) and Engel class (p = 0.04). Seizure control 1year after surgery significantly predicted survival of patients affected by LGG-related epilepsy in a large monocentric retrospective series. Future studies are needed to confirm these results and to assess if an epilepsy-surgical therapeutic approach may improve OS.

ATRXLoss Increases Sensitivity to Proton Radiotherapy Compared to X-Ray Radiotherapy in Glioma Stem Cells via Secondary Necrosis

Glioblastoma Multiforme (GBM-Grade IV) is the most aggressive form of glioma in the USA carrying only a 15 month median survival time. Although IDH1R132H is traditionally associated with improved glioma patient survival and clinical response to chemotherapy, astrocytoma (LGG) patients also harbor ATRXLoss, an inactivation of the ATRX chromatin remodeling protein previously shown to impair DNA damage repair via non-homologous end joining. The recent discovery of glioma stem cells (GSCs), a subpopulation of chemoradioresistant, self-renewable, tumor initiating cells known to promote tumor recurrence, presents a new target for therapeutic intervention. However, the mechanisms by which ATRXLoss contributes to GSC proton radiotherapy (PRT) sensitivity, a more tumor specific and cytotoxic form of radiation therapy than conventional X-rays (XRT), are not well understood. We hypothesize that ATRXLoss impairs GSC post-radiation viability by promoting secondary necrosis to a higher extent after PRT than XRT.Isogenic TS543-ATRXWT and TS543-ATRXLoss patient derived glioma cells were cultured as neurospheres and treated with 2-8 Gy XRT or PRT. GSC viability was quantified using the CellTiterGlo 3D assay 12 days after irradiation. The Annexin V apoptosis and necrosis assay was conducted every 8 hours up to 72 hours after irradiation. GSC self-renewal, based on neurosphere formation frequency, was quantified using extreme limiting dilution analysis (ELDA).ATRXLoss significantly decreased TS543 GSC viability after 2-8 Gy radiation therapy compared to ATRXWT (Unpaired t-test with Welsh's correction and Holm-Sidak's Multiple Comparisons Test P < 0.0001). TS543-ATRXLoss also significantly decreased GSC self-renewal over TS543-ATRXWT when subject to either 6 Gy PRT or XRT (Pairwise Pr (> χ2) < 0.01). Interestingly, PRT significantly reduced GSC viability to a higher extent than XRT in TS543-ATRXLoss GSCs, which demonstrates the effectiveness of PRT to treat ATRXLoss gliomas. Follow up studies confirmed that ATRXLoss sensitizes TS543 GSCs more extensively to the cytotoxic effects of PRT compared to XRT via the upregulation of secondary necrosis at 72 hours post-irradiation (Two-way ANOVA with Tukey's post-hoc Multiple Comparisons Test P < 0.0001).We conclude that ATRXLoss substantially contributes to PRT sensitivity in GSCs, thereby supporting the benefits of PRT for astrocytoma patients. Our future experiments will further elucidate the biological mechanisms by which ATRXLoss confers PRT sensitivity, especially via dsDNA damage.A.A.Garces: None. L.Bronk: None. K. Bhat: None. D.R.Grosshans: None.

Construction of a novel microRNA-based signature for predicting the prognosis of glioma

Background and purpose: Glioma is a frequent primary brain tumor. MicroRNAs (miRNA) have been shown to potentially play a crucial part in tumor development. Based on miRNAs and clinical factors, a model was constructed to predict the glioma prognosis. Methods: The miRNA expression profiles of glioma come from The Cancer Genome Atlas (TCGA, training group) and Chinese Glioma Genome Atlas (CGGA, validation group). Regression analyses of Cox and Lasso were applied to identity miRNAs associated with glioma prognosis in the TCGA database. The miRNAs were combined with clinical factors to construct individualized prognostic prediction models, whose performance was validated in the CGGA database. The role of miRNA in glioma development was investigated by in vitro experiments. Results: We identified five key miRNAs associated with glioma prognosis and constructed a prediction model. The area under ROC curve for predicting 3-year survival of glioma patients in the TCGA and CGGA groups was 0.844 and 0.770, respectively. The nomogram constructed using the miRNA risk scores and clinical factors showed high accuracy of prediction in the TCGA group (C-index of 0.820) and the CGGA group (C-index of 0.722). The miR-196b-5p altered the migration, proliferation, invasion, and apoptosis of glioma cells by regulating target genes, according to in vitro experiments. Conclusions: A miRNA-based individualized prognostic prediction model was constructed for glioma and miR-196b-5p was identified as a potential biomarker of glioma development.

USP30-AS1 contributes to mitochondrial quality control in glioblastoma cells

Glioblastoma is the most serious type of brain cancer with poor prognosis. Here, using the publicly available glioma database, we identified that USP30-AS1, an antisense lncRNA locating on the opposite strand of USP30 locus, is upregulated in human gliomas, particularly in high grade glioma. High level of USP30-AS1 is correlated with poor survival in both primary and recurrent glioma patients. USP30-AS1 regulates mitochondrial homeostasis and mitophagy in glioblastoma cells. Knockdown of USP30-AS1 decreases mitochondrial protein expression and mitochondrial mass, promotes mitochondrial uncoupler-induced mitophagy. However, USP30-AS1 does not regulate USP30 expression in a cis-regulatory manner. In summary, this study proposed that USP30-AS1 may serve as a valuable prognostic marker for gliomas. USP3-AS1 is a negative regulator of mitophagy and the regulatory effect is USP30-independent. USP30-AS1 mediated repression of mitophagy may contribute to the loss of mitochondrial homeostasis and tumor development in glioma.

Ki-67 expression as a prognostic factor of glioma in Indonesian population

Introduction: The most common neoplasms in the human brain is glioma that consisted of gial cells. The subjectivity in interpretation of glioma and difficulties to identify mitosis will affect the determination of tumor grade, therapy and prognosis of the patients. Immunostaining of Ki-67 represents the ability of tumor cells to proliferate and related to survival of the patient. Objective: The purpose of this study is to reveal the association of the Ki-67 expression and survival of glioma patients in Indonesia.

The influence of postoperative infections on the survival of glioma patients

Glioblastoma remains the most common and lethal brain tumor in adults with a poor prognosis. Thinking about immunological influences, the question if postoperative infections have any efforts on survival arises consistently. Of our knowledge, this is the first study to evaluate a large group of glioma patients with postoperative infections, itemized by intracranial, extracranial and systemic infection.

Neutrophil-to-lymphocyte ratio, factor VIII and antithrombin III: Inflammatory-clotting biomarkers in glioma

There is an urgent need for sufficiently sensitive, specific and routine biomarkers for glioma, tumour of glial cells. The main purpose of this study was to identify possible biomarkers in glioma comparing some routine coagulation factors and Neutrophil-to-lymphocyte ratio (NLR) among the following subgroups: a) glioma and MS patients, controls; b) non-recurrent and recurrent glioma patients. As a secondary endpoint we assessed if these markers could be predictive of overall (OS) and progression-free survival (PFS) in glioma patients.

Value of long non-coding RNA HAS2-AS1 as a diagnostic and prognostic marker of glioma

BackgroundGlioma presents high incidence and poor prognosis, and therefore more effective treatments are needed. Studies have confirmed that long non-coding RNAs (lncRNAs) basically regulate various human diseases including glioma. It has been theorized that HAS2-AS1 serves as an lncRNA to exert an oncogenic role in varying cancers. This study aimed to assess the value of lncRNA HAS2-AS1 as a diagnostic and prognostic marker for glioma. MethodsThe miRNA expression data and clinical data of glioma were downloaded from the TCGA database for differential analysis and survival analysis. In addition, pathological specimens and specimens of adjacent normal tissue from 80 patients with glioma were used to observe the expression of HAS2-AS1. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic ability and prognostic value of HAS2-AS1 in glioma. Meanwhile, a Kaplan–Meier survival curve was plotted to evaluate the survival of glioma patients with different HAS2-AS1 expression levels. ResultsHAS2-AS1 was significantly upregulated in glioma tissues compared with normal tissue. The survival curves showed that overexpression of HAS2-AS1 was associated with poor overall survival (OS) and progression-free survival (PFS). Several clinicopathological factors of glioma patients, including tumor size and WHO grade, were significantly correlated with HAS2-AS1 expression in tissues. The ROC curve showed an area under the curve (AUC) value of 0.863, indicating that HAS2-AS1 had good diagnostic value. The ROC curve for the predicted OS showed an AUC of 0.906, while the ROC curve for predicted PFS showed an AUC of 0.88. Both suggested that overexpression of HAS2-AS1 was associated with poor prognosis. ConclusionsNormal tissues could be clearly distinguished from glioma tissues based on HAS2-AS1 expression. Moreover, overexpression of HAS2-AS1 indicated poor prognosis in glioma patients. Therefore, HAS2-AS1 could be used as a diagnostic and prognostic marker for glioma.

LncRNA LINC00355 Acts as a Novel Biomarker and Promotes Glioma Biological Activities via the Regulation of miR-1225/FNDC3B.

Background Accumulating evidence has implicated long noncoding RNAs (lncRNAs) in glioma progression. Here, we aimed to explore the potential roles of a novel lncRNA, LINC00355, in glioma and to clarify the underlying mechanisms. Methods RT-PCR was used to examine the relative expressions of LINC00355 in glioma cell lines and specimen samples. The clinicopathological and prognostic significances of LINC00355 in glioma patients were statistically analyzed. To determine cell activities, CCK-8, clonogenic assays, flow cytometry, migration, and invasion assays were performed. Moreover, the potential mechanisms of LINC00355 were investigated by bioinformatics assays and luciferase reporter assays. Results LINC00355 expression was increased in glioma cell lines and specimens, and higher LINC00355 expression predicted advanced clinical progress and reduced overall survival and disease-free survival in glioma patients. Functionally, LINC00355 depletion promoted cell proliferation, invasion, and migration in glioma cells and induced apoptosis of glioma cells, whereas LINC00355 upregulation resulted in the opposite effects in vitro. Mechanistic assays revealed that LINC00355 as a sponge for miR-1225 repressed fibronectin type III domain-containing 3B (FNDC3B) expressions. Conclusion Our findings revealed the tumor-promotive roles of LINC00355 in the progression of glioma, indicating that LINC00355 exhibited ceRNA functions via modulating miR-1225/FNDC3B axis.

Non-invasively measured brain activity and radiological progression in diffuse glioma

Non-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.

Overexpression of GINS4 is associated with poor prognosis and survival in glioma patients

BackgroundGINS4, an indispensable component of the GINS complex, is vital for a variety of cancer. However, no known empirical research has focused on exploring relationships between GINS4 and glioma. Thus, this study aims to understand and explain the role of GINS4 in glioma.MethodFirst, we used the data in the CGGA, TCGA, GEO, GEPIA, and HPA databases to explore the expression level of GINS4 in glioma, the correlation between GINS4 expression and the clinical features of glioma, its impact on the survival of glioma patients, and verified the analysis results through RT-qPCR, IHC, and meta-analysis. Subsequently, GSEA enrichment analysis is used to find the potential molecular mechanism of GINS4 to promote the malignant process of glioma and the anti-glioma drugs that may target GINS4 screened by CMap analysis. Moreover, we further explored the influence of the GINS4 expression on the immune microenvironment of glioma patients through the TIMER database.ResultsOur results suggested that GINS4 was elevated in glioma, and the overexpression of GINS4 was connected with a vast number of clinical features. The next, GINS4 as an independent prognostic factor, which can result in an unfavorable prognosis of glioma. Once more, GINS4 may be participating in the oncogenesis of glioma through JAK-STAT signaling pathways, etc. 6-thioguanine, Doxazosin, and Emetine had potential value in the clinical application of drugs targeting GINS4. Finally, the expression exhibited a close relationship with some immune cells, especially Dendritic cells.ConclusionGINS4 is an independent prognostic factor that led to a poor prognosis of glioma. The present study revealed the probable underlying molecular mechanisms of GINS4 in glioma and provided a potential target for improving the prognosis of glioma.

Clinical Value of TXNDC12 Combined With IDH and 1p19q as Biomarkers for Prognosis of Glioma

Background: Glioma is the primary malignant tumor of the central nervous system and presents high mortality and disability rates under existing treatment measures. Thioredoxin domain-containing 12 (TXNDC12) has been shown to play an important role in various malignant tumors. Therefore, we explored the clinicopathological characteristics of TXNDC12 in glioma to bring to light new ideas in its treatment. Methods: We obtained data packages related to TXNDC12 expression status in gliomas from public databases. We analyzed glioma TXNDC12 expression and patient survival status and validated the above results using glioma specimens from our institution. Next, we analyzed the value of TXNDC12 in combination with 1p19q and isocitrate dehydrogenase (IDH) on the prognosis of glioma by regression model and receiver operating characteristic curve (ROC). Finally, we explored the function of related genes by GO analysis and KEGG analysis. Results: Compared with normal brain tissue, the expression of TXNDC12 in glioma cells, regarding both mRNA and protein levels, was significantly upregulated. The survival time of patients with high-expression of TXNDC12 in glioma cells was shortened. In the World Health Organization pathological classification, IDH status, 1p19q status, and IDH combined with 1p19q subgroups, the expression of TXNDC12 increased with the deterioration of the above indicators. Tumor local immune analysis showed that the immune cell infiltration in TXNDC12 high-expressing glioma tissue increased, the tumor purity was reduced. GO and KEGG analyses indicated that TXNDC12 may be involved in the malignant prognosis of glioma through glycosylation and antigen processing and presentation. Conclusion: We showed that TXNDC12 is significantly highly expressed in gliomas. This high expression predicts the poor prognosis of glioma patients and is related to the gliomas’ local immune microenvironment. As a tumor-related gene, TXNDC12 may be used as a new prognostic judgment molecule.

PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth.

Gliomas are the most lethal adult primary brain cancers. Recent advances in their molecular characterization have contributed to a better understanding of their pathophysiology, but there is still a need to identify key genes controling glioma cell proliferation and differentiation. The p21-activated kinases PAK1 and PAK2 play essential roles in cell division and brain development and are well-known oncogenes. In contrast, the role of PAK3 in cancer is poorly understood. It is known, however, that this gene is involved in brain ontogenesis and has been identified as a gene of the proneural subtype signature in glioblastomas. To better understand the role of PAK kinases in the pathophysiology of gliomas, we conducted expression analyses by querying multiple gene expression databases and analyzing primary human glioma samples. We next studied PAK3 expression upon differentiation in patient-derived cell lines (PDCLs) and the effects of PAK3 inhibition by lentiviral-mediated shRNA on glioma cell proliferation, differentiation and tumor growth. We show that contrary to PAK1 and PAK2, high PAK3 expression positively correlates with a longer survival of glioma patients. We also found that PAK3 displays differential expression patterns between glioma sub-groups with a higher expression in 1p/19q-codeleted oligodendrogliomas, and is highly expressed in tumors and PDCLs of the proneural subtype. In PDCLs, high PAK3 expression negatively correlated with proliferation and positively correlated with neuronal differentiation. Inhibition of PAK3 expression increased PDCL proliferation and glioma tumor growth in nude mice. Our results indicate that PAK3 plays a unique role among PAKs in glioma development and may represent a potential therapeutic target.

Aberrant nuclear lamina contributes to the malignancy of human gliomas

Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the malignant progress of gliomas. By virtue of integrated proteomics and genomics analyses as well as experimental validations, we identify three nuclear lamin genes (LMNA, LMNB1, and LMNB2) that are significantly upregulated in glioma tissues compared with normal brain tissues. We show that elevated expressions of LMNB1, LMNB2, and LMNA in glioma cells are highly associated with the rapid progression of the disease and the knockdown of LMNB1, LMNB2, and LMNA dramatically suppresses glioma progression in both in vitro and in vivo mouse models. Moreover, the repression of glioma cell growth by lamin knockdown is mediated by the pRb-mediated G1-S inhibition. On the contrary, overexpression of lamins in normal human astrocytes dramatically induced nuclear morphological aberrations and accelerated cell growth. Together, our multi-omics-based analysis has revealed a previously unrecognized role of lamin genes in gliomagenesis, providing a strong support for the key link between aberrant tumor nuclear shape and the survival of glioma patients. Based on these findings, lamins are proposed to be potential oncogene targets for therapeutic treatments of brain tumors.

Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment.

Glioma, characterized by infiltrative growth and treatment resistance, is regarded as the most prevalent intracranial malignant tumor. Due to its poor prognosis, accumulating investigation has been performed for improvement of overall survival (OS) and progression-free survival (PFS) in glioma patients. Valproic acid (VPA), one of the most common histone deacetylase inhibitors (HDACIs), has been detected to directly or synergistically exert inhibitory effects on glioma in vitro and in vivo. In this review, we generalize the latest advances of VPA in treating glioma and its underlying mechanisms and clinical implications, providing a clearer profile for clinical application of VPA as a therapeutic agent for glioma.