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Glioblastoma multiforme (GBM) is a common central neural system malignant tumor among adults. Alongside its microscopic spread, immunosuppression in the tumor microenvironment also induces its refractoriness, which makes immunotherapy for GBM particularly important. Unfortunately, traditional immune checkpoint inhibitors (ICIs) often show limited therapeutic effects in GBM clinical trials, and new therapeutic strategies or targets are urgently needed. TNFSF14/LIGHT is a novel immune checkpoint molecule that plays essential roles in both innate and acquired immunity. Despite recent advances in our understanding of the function of TNFSF14/LIGHT in a variety of cancer types, the clinical and immunological importance of TNFSF14/LIGHT in human gliomas has not been fully explained. Here, we employed a comprehensive in silico analysis with publicly available data to analyze the molecular and immune characteristics of TNFSF14/LIGHT to explore its feasibility as an immunotherapy target. Totally, 2215 glioma cases were enrolled in the current study. Immunohistochemistry staining based on patient tissues (n = 34) was performed for the validation. TNFSF14/LIGHT was expressed higher in higher-WHO-grade gliomas and mesenchymal subtypes, and it was sensitive as a prognostic marker in GBM and low-grade glioma (LGG). A nomogram prognostic model was established based on TNFSF14/LIGHT expression together with other risk factors. Additionally, Gene Ontology and pathway analysis revealed that TNFSF14/LIGHT participated in T-cell activities and inflammatory processes. Moreover, analysis based on the structure and interactions of TNFSF14/LIGHT revealed its mutation sites in tumors as well as crucial interacting proteins. Analysis of IMvigor210 indicated the role of TNFSF14/LIGHT in immunotherapy. Altogether, our results reveal an underlying role of TNFSF14/LIGHT as an immunotherapy target in GBM.

Background Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear. Methods Thirteen non-m6A-related neoantigen-coding lncRNAs were selected for analysis from the TransLnc database. Next, a neoantigen activation score (NAS) model was established based on the characteristics of the lncRNAs. Machine learning was employed to expand the model to two additional RNA-seq and two single-cell sequencing datasets for further validation. The DLpTCR algorithm was used to predict T cell receptor (TCR)-peptide binding probability. Results The non-m6A-related NAS model predicted patients’ overall survival outcomes more precisely than the m6A-related NAS model. Furthermore, the non-m6A-related NAS was positively correlated with tumor cells’ evolutionary level, immune infiltration, and antigen presentation. However, high NAS gliomas also showed more PD-L1 expression and high mutation frequencies of T-cell positive regulators. Interestingly, results of intercellular communication analysis suggest that T cell-high neoplastic cell interaction is weaker in both of the NAS groups which might arise from decreased IFNGR1 expression. Moreover, we identified unique TCR-peptide pairs present in all glioma samples based on peptides encoded by the 13 selected lncRNAs. And increased levels of neoantigen-active TCR patterns were found in high NAS gliomas. Conclusions Our work suggests that non-m6A-related neoantigen-coding lncRNAs play an essential role in glioma progression and that screened TCR clonotypes might provide potential avenues for chimeric antigen receptor T cell (CAR-T) therapy for gliomas.

Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as a therapeutic target candidate which significantly dysregulated iron metabolism in GBM cells. Overexpression of COPZ1 was associated with increasing tumor grade and poor prognosis in glioma patients based on analysis of expression data from the publicly available database The Cancer Genome Atlas (P P P

Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Ironically, studies have recently revealed that radiation can augment malignant progression, by promoting migration and invasion, which make the disease especially difficult to cure. Here, we investigated the anticancer effects of YM155, a purported radiosensitizer, in GBM cell lines.GBM cell lines U251 and U87 were treated with YM155 to assess cytotoxicity and activity of the molecule in vitro. Nude mice were implanted with cells to generate orthotopic xenografts for in vivo studies. Response of cells to treatment was examined using cell viability, immunofluorescence, wound healing, and the Transwell invasion assay. Molecules potentially mediating response were examined through western blot analysis, phospho-kinase arrays, and qPCR. Cells were transfected with siRNA knockdown and gene expression constructs to identify molecular mediators of response.YM155 reduced viability of U251 and U87 cells and enhanced radiosensitivity through inhibition of homologous recombination. Besides, YM155 decreased invasion caused by radiation and led to expression changes in molecular markers associated with EMT. STAT3 was one of 10 molecules identified on a phosphokinase array exhibiting significant change in phosphorylation under YM155 treatment. Transfection with STAT3 siRNAs or expression constructs demonstrated that EMT changes were achieved by inhibiting the phosphorylation of STAT3 and were survivin-independent. Finally, combining YM155 and radiation in orthotopic xenografts reduced growth and prolonged overall survival of animals.YM155 decreased radiation-induced invasion in GBM cell lines in vitro and in vivo through inhibition of STAT3.

Proteolipid protein 2 (PLP2) is an integral ion channel membrane protein of the endoplasmic reticulum. The protein has been shown to be highly expressed in many cancer types, but its importance in glioma progression is poorly understood. Using publicly available datasets (Rembrandt, TCGA and CGGA), we found that the expression of PLP2 was significantly higher in high‐grade gliomas than in low‐grade gliomas. We confirmed these results at the protein level through IHC staining of high‐grade (n = 56) and low‐grade glioma biopsies (n = 16). Kaplan‐Meier analysis demonstrated that increased PLP2 expression was associated with poorer patient survival. In functional experiments, siRNA and shRNA PLP2 knockdown induced ER stress and increased apoptosis and autophagy in U87 and U251 glioma cell lines. Inhibition of autophagy with chloroquine augmented apoptotic cell death in U87‐ and U251‐siPLP2 cells. Finally, intracranial xenografts derived from U87‐ and U251‐shPLP2 cells revealed that loss of PLP2 reduced glioma growth in vivo. Our results therefore indicate that increased PLP2 expression promotes GBM growth and that PLP2 represents a potential future therapeutic target. publishedVersion

Malignant gliomas including Glioblastoma (GBM) are characterized by extensive diffuse tumor cell infiltration throughout the brain, which represents a major challenge in clinical disease management. While surgical resection is beneficial for patient outcome, it is well recognized that tumor cells at the invasive front or beyond stay behind and constitute a major source of tumor recurrence. Invasive glioma cells also represent a difficult therapeutic target since they are localized within normal functional brain areas with an intact blood brain barrier (BBB), thereby excluding most systemic drug treatments. Cell movement is mediated via the actin cytoskeleton where corresponding membrane protrusions play essential roles. This review provides an overview of the various paths of glioma cell invasion and underlines the specific aspects of the brain microenvironment. We highlight recent insight into tumor microtubes, neuro-glioma synapses and tumor metabolism which can regulate collective invasion processes. We also focus on the deregulation of actin cytoskeleton-related components in the context of glioma invasion, a deregulation that may be controlled by genomic alterations in tumor cells as well as by various external factors, including extracellular matrix (ECM) components and non-malignant stromal cells. Finally we critically assess the challenges and opportunities for therapeutically targeting glioma cell invasion.

In almost all patients, malignant glioma recurs following initial treatment with maximal safe resection, conformal radiotherapy, and temozolomide. This review describes the many options for treatment of recurrent malignant gliomas, including reoperation, alternating electric field therapy, chemotherapy, stereotactic radiotherapy or radiosurgery, or some combination of these modalities, presenting the evidence for each approach. No standard of care has been established, though the antiangiogenic agent, bevacizumab; stereotactic radiotherapy or radiosurgery; and, perhaps, combined treatment with these 2 modalities appear to offer modest benefits over other approaches. Clearly, randomized trials of these options would be advantageous, and novel, more efficacious approaches are urgently needed.

BACKGROUND: Gliomas are the most common primary malignant brain tumor. Diffuse low-grade and intermediate-grade gliomas, which together compose the lower-grade gliomas (LGGs; World Health Organization [WHO] grades II and III), present a therapeutic challenge to physicians due to the heterogeneity of their clinical behavior. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a survival nomogram for patients with newly diagnosed LGG. METHODS: Data were obtained for newly diagnosed LGG patients from The Cancer Genome Atlas (TCGA) and the Ohio Brain Tumor Study (OBTS) with the following variables: tumor grade (II or III), age at diagnosis, sex, Karnofsky performance status (KPS), and molecular subtype (IDH mutant with 1p/19q codeletion [IDHmut-codel], IDH mutant without 1p/19q codeletion, and IDH wild-type). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using TCGA data and independently validated using the OBTS data. Models were internally validated using 10-fold cross-validation and externally validated with calibration curves. RESULTS: A final nomogram was validated for newly diagnosed LGG. Factors that increased the probability of survival included grade II tumor, younger age at diagnosis, having a high KPS, and the IDHmut-codel molecular subtype. CONCLUSIONS: A nomogram that calculates individualized survival probabilities for patients with newly diagnosed LGG could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free online software for implementing this nomogram is provided: https://hgittleman.shinyapps.io/LGG_Nomogram_H_Gittleman/. KEY POINTS: 1. A survival nomogram for lower-grade glioma patients has been developed and externally validated. 2. Free online software for implementing this nomogram is provided allowing for ease of use by practicing health care providers.

Recent evidence suggests that dysregulation of iron regulatory factors may play essential roles in cancer pathophysiology. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a metalloreductase, which is vital for cellular iron uptake and homeostasis. However, the clinical significance and function of STEAP3 in the development of human gliomas remain unclear. Through analysis of publicly available databases, we found that STEAP3 was highly expressed in malignant gliomas, especially in the mesenchymal glioma molecular subtype and isocitrate dehydrogenase 1/2 (IDH1/2) wild-type gliomas. Expression levels of STEAP3 in gliomas correlated inversely with patient overall survival (OS) and served as an independent prognostic marker by multivariate Cox regression analysis. In functional assays performed with RNA knockdown, loss of STEAP3 attenuated aggressive phenotypes in glioma cells, including cell proliferation, invasion, and sphere formation in vitro and tumor growth in vivo. Finally, STEAP3 drives these activities by inducing mesenchymal transition, promoting transferrin receptor (TfR) expression, and activating STAT3-FoxM1 axis signaling. Taken together, these results indicate that STEAP3 functions as an oncogenic mediator in glioma progression and is thus a potential therapeutic target for the treatment of the disease.

Bufalin, a cardiotonic steroid found in the venom of the Chinese toad Bufo gargarizan, has been shown to inhibit the growth of human cancers, such as colon and bladder. Here, we investigated the response of U251 and U87MG glioblastoma (GBM) cell lines to bufalin in vitro and found that bufalin impaired several biological processes. First, in both U251 and U87 MG, bufalin reduced cell proliferation and induced a G2/M cell cycle arrest (∼10% vs∼30%, untreated vs treated cells, respectively). Second, bufalin disrupted the mitochondrial membrane potential, leading to reduced oxygen consumption and ATP production. Third, homologous recombination (HR) efficiency was reduced by∼40% in both cell lines in the presence of bufalin. At the molecular level, bufalin led to decreased RAD51 protein, a central player in HR, and increased γ-H2AX, a marker for the presence of DNA double strand breaks. Finally, bufalin was additive with radiation in the treatment of GBM cells in vitro. Cell death increased significantly under combination treatment compared to radiation treatment alone. Our findings indicated that bufalin led to reduced mitochondrial and DNA repair function and therefore, might be a promising therapeutic drug to increase the sensitivity of GBM cells to radiotherapy.

The Ras-related GTP-binding protein (RAB) family plays an important role in regulating signal transduction and cellular processes including vesicle transport, cytoskeleton formation and membrane trafficking. More recently, several RAB members have been reported to promote tumorigenesis in many types of cancers. However, the clinical significance and potential function of RAB43 in gliomas remain unclear. Herein, we found that RAB43 was upregulated and positively correlated with the grade of progression in glioma patients by in silico analysis and immunohistochemistry (IHC). Patients with high RAB43 displayed worse clinical outcomes in comparison to those with low RAB43. RAB43 was also highly expressed in mesenchymal and G3 subtypes, and isocitrate dehydrogenase 1 (IDH1) wild-type gliomas. Moreover, transcriptomic analyses via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that RAB43‑related gene sets were mainly involved in the regulation of cell adhesion and cell migration processes. Further investigation indicated that RAB43 downregulation significantly suppressed the migratory and invasive ability of glioma cells, as well as decreased the expression of epithelial-mesenchymal transition (EMT) markers (N-cadherin, vimentin and Snail). In conclusion, a high level of RAB43 was significantly associated with the malignant phenotypes of gliomas, which suggests that RAB43 may serve as a novel biomarker and a potential therapeutic target for gliomas.

Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24‐hydroxylase (CYP46A1), a brain‐specific enzyme responsible for the elimination of cholesterol through the conversion of cholesterol into 24(S)‐hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared with normal brain tissue. A reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis in human gliomas. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. RNA‐seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz, an activator of CYP46A1 that is known to penetrate the blood–brain barrier, inhibited GBM growth in vivo. Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target., Loss of CYP46A1 partially caused excessive cholesterol accumulation in glioblastoma cells contributing to the maintenance of tumour cell viability and a malignant state. Efavirenz, an anti‐HIV drug, crosses the BBB and shows anti‐tumor effect though activation of the CYP46A1/24OHC axis.

Background Dysregulation of immune checkpoint molecules leads to immune evasion in human tumours but has become a viable target for tumour therapy. Here, we examined expression of Herpes virus entry mediator (HVEM), an immune checkpoint molecule, in human glioblastoma (GBM) to assess its potential as a molecular target for treatment. Methods Molecular and clinical data from publicly available genomic databases containing WHO grade II-IV human glioma cases (n = 1866) were analyzed. Immunohistochemistry was applied to assess HVEM protein levels in primary tumour sections. Statistical analysis was performed using Matlab and R language. Findings HVEM was found to be elevated in aggressive gliomas, particularly in the mesenchymal and isocitrate dehydrogenase (IDH) wild-type molecular subtypes of GBM. HVEMhigh tumours tended to be associated with amplification of EGFR and loss of PTEN, while HVEMlow tumours harbored mutations in IDH1 (93%). HVEM exhibited potential as a prognostic marker based on Cox regression and nomogram models. HVEM displayed intra-tumour heterogeneity and was more highly expressed in peri-necrotic and microvascular regions. Gene ontology and pathway analysis revealed enrichment of HVEM in multiple immune regulatory processes, such as suppression of T cell mediated immunity in GBM. Finally, in cell lineage analysis, HVEM was found to be tightly associated with several infiltrating immune and stromal cell types which localized to the tumour microenvironment. Interpretation Our data highlights the importance of HVEM in the development of GBM and as a potential molecular target in combination with current immune checkpoint blockades for treatment of GBM.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates lymphocyte trafficking, glial cell activation, vasoconstriction, endothelial barrier function, and neuronal death pathways in the brain. Research has increasingly implicated S1P in the pathology of cerebral ischemia reperfusion (IR) injury. As a high-affinity agonist of S1P receptor, fingolimod exhibits excellent neuroprotective effects against ischemic challenge both in vivo and in vitro. By summarizing recent progress on how S1P participates in the development of brain IR injury, this review identifies potential therapeutic targets for the treatment of brain IR injury.

Background Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Here, we examined the role of GOLM1 in the development of human glioma. Methods qRT-PCR, immunohistochemistry, and western blot analysis were performed to evaluate GOLM1 levels in cell lines and a cohort of primary human glioma and non-neoplastic brain tissue samples. Glioma cell lines were modified with lentiviral constructs expressing short hairpin RNAs targeting GOLM1 or overexpressing the protein to assess function in proliferation, viability, and migration and invasion in vitro using EdU, CCK8, clone-forming, Transwell assays, 3D tumor spheroid invasion assay and in vivo in orthotopic implantations. Protein lysates were used to screen a membrane-based antibody array to identify kinases mediated by GOLM1. Specific inhibitors of PDGFRα (AG1296) and AKT (MK-2206) were used to examine the regulation of PDGFA/PDGFRα on GOLM1 and the underlying pathway respectively. Results qRT-PCR, immunohistochemistry and western blot analysis revealed GOLM1 expression to be elevated in glioma tissues and cell lines. Silencing of GOLM1 attenuated proliferation, migration, and invasion of U251, A172 and P3#GBM (primary glioma) cells, while overexpression of GOLM1 enhanced malignant behavior of U87MG cells. We further demonstrated that activation of AKT is the driving force of GOLM1-promoted glioma progression. The last finding of this research belongs to the regulation of PDGFA/PDGFRα on GOLM1, while GOLM1 was also a key element of PDGFA/PDGFRα-mediated activation of AKT, as well as the progression of glioma cells. Conclusions PDGFA/PDGFRα-regulated GOLM1 promotes glioma progression possibly through activation of a key signaling kinase, AKT. GOLM1 interference may therefore provide a novel therapeutic target and improve the efficacy of glioma treatment, particularly in the case of the proneural molecular subtype of human glioma. Electronic supplementary material The online version of this article (10.1186/s13046-017-0665-3) contains supplementary material, which is available to authorized users.

Background Transgelin-2 (TAGLN2) is a member of the calponin family of actin-bundling proteins that is involved in the regulation of cell morphology, motility, and cell transformation. Here, the clinical significance and potential function of TAGLN2 in malignant gliomas were investigated. Methods Molecular and clinical data was obtained from The Cancer Genome Atlas (TCGA) database. Gene ontology and pathway analysis was used to predict potential functions of TAGLN2. RNA knockdown was performed using siRNA or lentiviral contructs in U87MG and U251 glioma cell lines. Cells were characterized in vitro or implanted in vivo to generate orthotopic xenografts in order to assess molecular status, cell proliferation/survival, and invasion by Western blotting, flow cytometry, and 3D tumor spheroid invasion assay, respectively. Results Increased TAGLN2 expression was associated with increasing tumor grade (P

Increased Actin-like 6A (ACTL6A) expression has been implicated in the development of diverse cancers and recently associated with the Hippo signaling pathway, which is known to regulate biological properties, including proliferation, tissue regeneration, stem cell biology, as well as tumorigenesis. Here we first show that ACTL6A is upregulated in human gliomas and its expression is associated with glioma patient survival. ACTL6A promotes malignant behaviors of glioma cells in vitro and in orthotopic xenograft model. In co-immunoprecipitation assays, we discover that ACTL6A physically associated with YAP/TAZ and furthermore disrupts the interaction between YAP and β-TrCP E3 ubiquitin ligase, which promotes YAP protein degradation. Moreover, effects of ACTL6A on glioma cells proliferation, migration, and invasion could be mediated by YAP/TAZ. These data indicate that ACTL6A may contribute to cancer progression by stabilizing YAP/TAZ and therefore provide a novel therapeutic target for the treatment of human gliomas.

Background: Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo. Methods: U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. Results: IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 μM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models. Conclusions: This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients. publishedVersion

Background The coiled-coil domain is a structural motif found in proteins that participate in a variety of biological processes. Aberrant expression of such proteins has been shown to be associated with the malignant behavior of human cancers. In this study, we investigated the role of a specific family member, coiled-coil domain containing 109B (CCDC109B), in human gliomas. Methods and results We confirmed that CCDC109B was highly expressed in high grade gliomas (HGG; WHO III–IV) using immunofluorescence, western blot analysis, immunohistochemistry (IHC) and open databases. Through Cox regression analysis of The Cancer Genome Atlas (TCGA) database, we found that the expression levels of CCDC109B were inversely correlated with patient overall survival and it could serve as a prognostic marker. Then, a serious of cell functional assays were performed in human glioma cell lines, U87MG and U251, which indicated that silencing of CCDC109B attenuated glioma proliferation and migration/invasion both in vitro and in vivo. Notably, IHC staining in primary glioma samples interestingly revealed localization of elevated CCDC109B expression in necrotic areas which are typically hypoxic. Moreover, small interfering RNA (siRNA) and specific inhibiters of HIF1α led to decreased expression of CCDC109B in vitro and in vivo. Transwell assay further showed that CCDC109B is a critical factor in mediating HIF1α-induced glioma cell migration and invasion. Conclusion Our study elucidated a role for CCDC109B as an oncogene and a prognostic marker in human gliomas. CCDC109B may provide a novel therapeutic target for the treatment of human glioma. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1266-9) contains supplementary material, which is available to authorized users.

The epidermal growth factor (EGF) pathway has been reported as canonical causes in cancer development. Meanwhile, the involvement of C23 in multiple signaling pathways has been also investigated (Lv et al., 2014). However, the effect of C23 on EGF pathway in glioblastoma is not fully characterized. In the present study, C23 and the epidermal growth factor receptor (EGFR) of U251 cell line were inhibited by C23 and EGFR antibodies, respectively; and then C23 and EGFR siRNAs were used to knock down endogenous C23 and EGFR, respectively. In addition, soft-agar and MTT assay were also introduced. Compared with control, either C23 or EGFR antibodies efficiently repressed the phosphorylation levels of ERK1/2 (p

Malignant glioma is notorious for its aggressiveness and poor prognosis, and the invasiveness of glioma cells is the major obstacle. Accumulating evidence indicates that kinesin superfamily proteins (KIFs) may play key roles in tumor invasiveness, but the mechanisms remained unresolved. Our previous study demonstrated that membrane type 1-matrix metalloproteinase (MT1-MMP) was involved in Kinesin family member 1B (KIF1B)-modulated invasion of gastric cancer cells. Therefore, the role of KIF1B in glioma cell invasion and its relationship with MT1-MMP were explored in the present study. We found that aberrantly increased expression of KIF1B was associated with worse WHO pathological classification and Karnofsky performance status (KPS), which also showed a trend towards worse prognosis. In the transwell assay, knockdown of KIF1B using siRNA repressed U87MG and A172 glioma cell migration and invasion. Silencing KIF1B inhibited expression of membranal MT1-MMP; however, the amount of MT1-MMP in the whole cell lysate was not affected. In conclusion, targeting KIF1B may be an option for anti-invasive therapies targeting glioma.

In recent years, CD133 has been identified as a cancer stem cell (CSC) marker in gliomas. Nevertheless, the clinical and prognostic value of CD133 in glioma patients remains controversial. Therefore, we conducted a systematic meta-analysis to evaluate the correlation of CD133 with World Health Organization (WHO) grade, age, gender, overall survival (OS), and progression-free survival (PFS) in glioma patients. Eligible studies on this subject were included, and then pooled odd ratios (ORs) and hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) were estimated. Publication bias was assessed by the funnel plots, and heterogeneity and sensitivity were analyzed as well. In the present study, 21 articles with the total number of 1535 patients were included. High expression of CD133 in glioma patients was associated with high WHO grade (III + IV) (n = 11, OR 5.10, 95 % CI 2.99–8.69; p = 0.000), rather than age (n = 4, OR 2.54, 95 % CI 0.68–9.52; p = 0.167) and gender (n = 4, OR 0.71, 95 % CI 0.21–2.45; p = 0.587). In addition, survival analysis demonstrated a significant association between CD133 high expression and poor 2-year OS (n = 11, HR 2.18, 95 % CI 1.29–3.7; p = 0.004), 5-year OS (n = 4, HR 10.39, 95 % CI 2.59–41.63; p = 0.001), as well as PFS (n = 10, HR 2.34, 95 % CI 1.62–3.37; p = 0.000). Taken together, this study suggests that CD133 expression correlates to higher grade of gliomas and worse prognosis in glioma patients. Thus, CD133 could be recommended as a useful pathological and prognostic biomarker in clinical practice.

Up to now, survivin has been recommended as a prognostic and diagnostic indicator in glioma patients. However, there are still many controversies. Here, a meta-analysis was conducted to draw a more definitive conclusion on the correlation of survivin with overall survival (OS), age, gender, and WHO grade. Eligible studies were available through careful assessment, and then pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated. Funnel plots were introduced to evaluate the publication bias. Additionally, heterogeneity and sensitivity were also evaluated. In the present meta-analysis, 15 eligible studies with a total of 1,089 patients were incorporated. Survivin expression in gliomas correlated with 2-year OS (n = 8; HR 0.17, 95% CI 0.11-0.26) and 5-year OS (n = 7; HR 0.12, 95% CI 0.07-0.22) in patients. In addition, a fixed-effect model revealed a significant association between survivin and age (male/+; OR 2.10, 95% CI 1.44-3.05) and survivin and WHO grade (I+II/+; OR 0.27, 95% CI 0.19-0.38). No heterogeneity was observed across all studies. According to Begg's and Egger's test and funnel plot, no publication bias was reported. Taken together, our meta-analysis suggests that survivin expression is associated with poor survival, older age, and higher WHO grade and could be suggested as a useful prognostic and diagnostic biomarker, or an effective therapy target.

The transforming growth factor β (TGF-β) pathway plays a key role in oncogenesis of advanced cancers, involving the non-Smad and Smad pathways. Meanwhile, nucleolin on the cell surface has been also reported to affect activation of signaling pathways. However, the effect of cell surface nucleolin on TGF-β pathway in glioblastoma is not still understood. Here, using antibodies of nucleolin and TGF-β receptor I (TβR-I), we observed blocking of either nucleolin or TβR-I inhibited the phosphorylation of CrkL, Erk1/2, and Smad2. Using nucleolin siRNA, nucleolin knockdown was also identified to suppress the expression of p-CrkL, p-Erk1/2, and p-Smad2. Furthermore, immunoprecipitation revealed the interaction between cell surface nucleolin and TβR-I on the U87 cell membrane. In addition, U87 cell wound-healing, soft-agar and MTT assay also showed si-nucleolin could obviously impair wound closure (p 0.001), colony formation (p 0.001) and cell growth (p 0.001). In conclusion, nucleolin promotes and regulates the TGF-β pathway by interacting with TβR-I and is required for initiation and activation of TGF-β signaling. Thus, nucleolin could be a key factor in glioblastoma pathogenesis and considered a therapeutic target, which may also mediate more signaling pathways.

Aims The clinical relevance of expression of chemokine receptor 4 (CXCR4) in colorectal carcinoma (CRC) remains controversial; our aim was to identify the precise relationship of CXCR4 to prognosis and clinicopathological features. Methods and results A meta-analysis was performed. Original data included the hazard ratios (HRs) of recurrence-free survival (RFS), overall survival (OS) and odds ratio (OR) in CRC patients. We pooled HR/OR with 95% confidence intervals (CIs) to estimate the hazard. A total of 20 published studies (including 2253 patients) were eligible. RFS and OS were related significantly to CXCR4 expression, with HRs 1.62 (95% CI 1.24–2.11; P