LRIG3 Suppresses Angiogenesis by Regulating the PI3K/AKT/VEGFA Signaling Pathway in Glioma.

High levels of microvessel density (MVD) indicate poor prognosis in patients with malignant glioma. Leucine-rich repeats and immunoglobulin-like domains (LRIG) 3, a potential tumor suppressor, plays an important role in tumor progression and may serve as a biomarker in many human cancers. However, its role and underlying mechanism of action in glioma angiogenesis remain unclear. In the present study, we used loss- and gain-of-function assays to show that LRIG3 significantly suppressed glioma-induced angiogenesis, both in vitro and in vivo. Mechanistically, LRIG3 inhibited activation of the PI3K/AKT signaling pathway, downregulating vascular endothelial growth factor A (VEGFA) in glioma cells, thereby inhibiting angiogenesis. Notably, LRIG3 had a significant negative correlation with VEGFA expression in glioma tissues. Taken together, our results suggest that LRIG3 is a novel regulator of glioma angiogenesis and may be a promising option for developing anti-angiogenic therapy.

A Candidate Prognostic Biomarker Complement Factor I Promotes Malignant Progression in Glioma.

Objectives: Glioma is the most common and aggressive type of primary central nervous system (CNS) tumor in adults and is associated with substantial mortality rates. The aim of our study was to evaluate the prognostic significance and function of the complement factor I (CFI) in glioma. Materials and Methods: The expression levels of CFI in glioma tissues and the survival of the CFIhigh and CFIlow patient groups were analyzed using The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx). The correlation between CFI expression and clinicopathological features of glioma was determined by univariate and multivariate Cox regression analyses in the Chinese Glioma Genome Atlas (CGGA) database. The functional role of CFI in glioma was established through routine in vitro and in vivo assays. Results: CFI is overexpressed in glioma and its high levels correlated with poor outcomes in both TCGA and CGGA datasets. Furthermore, CFI was identified as an independent prognostic factor of glioma in the CGGA database. CFI knockdown in glioma cell lines inhibited growth in vitro and in vivo, whereas its ectopic expression increased glioma cell proliferation, migration, and invasion in vitro. CFI protein levels were also significantly higher in the glioma tissues resected from patients and correlated to worse prognosis. Conclusions: CFI is a potential prognostic biomarker in glioma and drives malignant progression.

USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells.

The mesenchymal (MES) subtype of glioblastoma (GBM) stem cells (GSCs) represents a subpopulation of cancer cells that are notorious for their highly aggressive nature and resistance to conventional therapy. Aldehyde dehydrogenase 1A3 (ALDH1A3) has been recently suggested as a key determinant for the maintenance of MES features of GSCs. However, the mechanisms underpinning aberrant ALDH1A3 expression remain elusive. Here, we identified ubiquitin-specific protease 9X (USP9X) as a bona fide deubiquitinase of ALDH1A3 in MES GSCs. USP9X interacted with, depolyubiquitylated, and stabilized ALDH1A3. Moreover, we showed that FACS-sorted USP9Xhi cells were enriched for MES GSCs with high ALDH1A3 activity and potent tumorigenic capacity. Depletion of USP9X markedly downregulated ALDH1A3, resulting in a loss of self-renewal and tumorigenic capacity of MES GSCs, which could be largely rescued by ectopic expression of ALDH1A3. Furthermore, we demonstrated that the USP9X inhibitor WP1130 induced ALDH1A3 degradation and showed marked therapeutic efficacy in MES GSC-derived orthotopic xenograft models. Additionally, USP9X strongly correlated with ALDH1A3 expression in primary human GBM samples and had a prognostic value for patients with the MES subgroup. Collectively, our findings unveil USP9X as a key deubiquitinase for ALDH1A3 protein stabilization and a potential target for GSC-directed therapy.

A Meta-Analysis of Endoscopic Microvascular Decompression versus Microscopic Microvascular Decompression for the Treatment for Cranial Nerve Syndrome Caused by Vascular Compression.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of endoscopic microvascular decompression (E-MVD) and microscopic microvascular decompression (M-MVD) for the treatment for cranial nerve syndrome caused by vascular compression, including primary trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia. METHODS: A systematic search of the online databases, including PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China Biology Medicine disc, and China National Knowledge Infrastructure, was performed from January 1966 to March 2018. The language of the included literature was not limited. Relevant outcomes of perioperative safety and postoperative efficacy were considered for meta-analysis. Single-arm and cumulative meta-analyses were also conducted. All the outcomes were calculated as odds ratios (ORs) with 95% confidence intervals using R language. RESULTS: A total of 9 studies involving 1093 (E-MVD [543] vs. M-MVD [550]) patients were included for analysis in our study. The recent remission rate (92% vs. 86%; OR, 1.71; P = 0.0089), offending vessel discovery rate (99% vs. 95%; OR 2.76, P = 0.0061), and long-term remission rate (97% vs. 87%; OR 4.59, P = 0.0036) were significantly higher in patients who underwent E-MVD than in those who underwent M-MVD, whereas perioperative complications (23% vs. 35%; OR 0.56, P < 0.0001) were significantly lower in patients who underwent E-MVD. CONCLUSIONS: This meta-analysis confirms that E-MVD is superior to M-MVD both in perioperative and postoperative efficacy (short- and long-term), and therefore it should be considered as an appropriate treatment choice for patients with neuralgia and hemifacial spasm.

The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling.

The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol κ, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide treatment. Overexpression of Pol κ in temozolomide-sensitive GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol κ disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell-cycle re-entry and progression. Further investigation of the relationship between Pol κ and temozolomide revealed that Pol κ inactivation facilitated temozolomide-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of temozolomide resistance. Moreover, overexpression of Rad17 in Pol κ-depleted GBM cells restored HR efficiency, promoted the clearance of temozolomide-induced DNA breaks, and desensitized cells to the cytotoxic effects of temozolomide observed in the absence of Pol κ. Finally, we found that Pol κ overexpression correlated with poor prognosis in GBM patients undergoing temozolomide therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to temozolomide and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance. Cancer Res; 76(8); 2340-53. ©2016 AACR.

c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma.

Resistance to temozolomide poses a major clinical challenge in glioblastoma multiforme treatment, and the mechanisms underlying the development of temozolomide resistance remain poorly understood. Enhanced DNA repair and mutagenesis can allow tumour cells to survive, contributing to resistance and tumour recurrence. Here, using recurrent temozolomide-refractory glioblastoma specimens, temozolomide-resistant cells, and resistant-xenograft models, we report that loss of miR-29c via c-Myc drives the acquisition of temozolomide resistance through enhancement of REV3L-mediated DNA repair and mutagenesis in glioblastoma. Importantly, disruption of c-Myc/miR-29c/REV3L signalling may have dual anticancer effects, sensitizing the resistant tumours to therapy as well as preventing the emergence of acquired temozolomide resistance. Our findings suggest a rationale for targeting the c-Myc/miR-29c/REV3L signalling pathway as a promising therapeutic approach for glioblastoma, even in recurrent, treatment-refractory settings.

Thermoelectric properties of Sb2Te3 thin films by electron beam evaporation.

This study applies the thermoelectric grains of Sb2Te3 on conductive glass to evaporate Sb2Te3 thin films by the electron beam evaporation method. Through experimental tests with different evaporation process parameters and film annealing conditions, thin films with better Seebeck coefficient, resistivity (p) and power fact (PF) can be obtained. Experimental results show that when thin films are annealed, their defects can be decreased accordingly, and carrier mobility can be enhanced to further elevate the conductivity of thin films. When the substrate temperature is set at 200 degrees C to fabricate Sb2Te3 thin films by the evaporation process and by annealing at 220 degrees C for 60 minutes, the Seebeck coefficient of Sb2Te3 thin films increase from 87.6 microV/K to 177.7 microV/K; resistivity falls from 6.21 m ohms-cm to 2.53 m ohms-cm and PF can achieve the maximum value of 1.24 10(-3) W/K2 m. Finally, this study attempts to add indium (In) to Sb2Te3 thin films. Indium has been successfully fabricated In3SbTe, thin films. This study also analyzes the effects of In on the thermoelectric properties of In3SbTe2 thin films.