Neuroligin-3 (NLGN3) is necessary and sufficient to promote glioma cell growth. The recruitment of Gαi1/3 to the ligand-activated receptor tyrosine kinases (RTKs) is essential for mediating oncogenic signaling.

Purpose: The microRNA (miRNA) profile changes in the tumor-associated macrophages. However, the role of miR-106b-5p in the glioblastoma-associated macrophages is poorly understood. Materials and Methods: In our study, miR-106b-5p and M2 macrophage markers were detected by qRT-PCR and Western blotting in THP1 cells, with the conditioned medium from U251 cells or M2 macrophages in response to IL-4 stimulation and M1 macrophages stimulated by LPS and IFN-γ. IFN regulatory factor (IRF1) was identified as a target of miR-106b-5p in the glioma infiltrating macrophages by luciferase reporter assay. The molecular mechanisms involved in the miR-106b-5p-mediated regulation of M2 polarization were clarified by shRNA knockdown assay. Results: Our results showed miR-106b-5p expression was upregulated in glioma-infiltrating macrophages. miR-106b-5p regulated M2 polarization of glioma infiltrating macrophages and enhanced the growth of glioma-infiltrating macrophages. IRF1 was identified as a target of miR-106b-5p. Furthermore, miR-106b-5p inhibited IRF1 expression by targeting IRF1/IFN-β pathway to promote M2 polarization of macrophages. Conclusion: miR-106b-5p may inhibit IRF1/IFN-β signaling to promote M2 macrophage polarization of glioblastoma, and it may become a novel target for the treatment of glioblastoma.

TIMM44 (translocase of inner mitochondrial membrane 44) is essential for the maintenance of mitochondrial functions. Bioinformatics studies and results from the local high-grade glioma tissues showed that TIMM44 mRNA and protein levels are elevated in glioma, correlating with poor overall survival. Mitochondrial TIMM44 upregulation was also detected in patient-derived primary glioma cells and immortalized cell line. In primary and established glioma cells, TIMM44 depletion, using the lentiviral shRNA strategy or the CRISPR/Cas9 knockout (KO) method, robustly inhibited cell viability, proliferation and migration. Moreover, TIMM44 silencing/KO resulted in mitochondrial complex I inhibition, ATP depletion, mitochondrial membrane potential reduction, oxidative stress and DNA damage, and eventually provoked apoptosis. Conversely, ectopic overexpression of TIMM44 augmented glioma cell proliferation and migration. TIMM44 upregulation in glioma is possibly due to increased TIMM44 transcriptional machinery by the transcription factor GATA3 in a YME1L (YME1 Like 1 ATPase)-dependent manner. In vivo, the growth of subcutaneous glioma xenografts was suppressed after intratumoral injection of TIMM44 shRNA adeno-associated virus (AAV). TIMM44 depletion, ATP reduction, oxidative injury and apoptosis were detected in TIMM44 shRNA AAV-injected glioma xenografts. Moreover, the intracranial growth of TIMM44 KO glioma cells in the mouse brain was largely inhibited. Together, overexpressed TIMM44 could be a novel and promising therapeutic target of human glioma.

Purpose: To date, there are no systemic treatment options for patients with recurrent or refractory meningioma. Experimental Design: To identify effective drugs, we performed a large-scale drug screening using FDA-approved drugs on several meningioma cell lines. The impact of the top four compounds was assessed on cell viability, proliferation, colony formation, migration, and apoptosis. In addition, the antineoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model. Results: Analyses of the viability of meningioma cells treated with 119 antineoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug–response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. Eighty drugs, including 15 alkylating agents, 14 antimetabolites, and 13 tyrosine kinase inhibitors, were classified as resistant (IC50 > Cmax). The sensitive drug–response group (n = 29, IC50 < Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 value of the four most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nmol/L. Most of them caused cell-cycle arrest in the G2–M-phase and induced apoptosis. Furthermore, all drugs except romidepsin significantly inhibited tumor growth in vivo. The strongest antineoplastic effect was observed for ixabepilone, which reduced tumor volume by 86%. Conclusions: In summary, a large-scale drug screening provides a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent antineoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation.

Glioma is the most commonly diagnosed primary intracranial malignant tumor with rapid growth, easy recurrence and thus poor prognosis. In the present study, the role of kinesin‑12 (KIF15) in glioma was revealed. Immunohistochemical staining and western blot analysis were used to detect the protein expression. An MTT assay was performed to evaluate cell proliferation. Flow cytometric analysis was utilized to assess cell apoptosis and the cell cycle. A mouse xenograft model was constructed for in vivo study. The results indicated that KIF15 was significantly upregulated in glioma tumor tissues and positively correlated with pathological staging, recurrence risk and poor prognosis. Silencing of KIF15 could inhibit cell proliferation and stemness of glioma cells, arrest cells in the G2 phase and induce cell apoptosis. The in vivo study verified the inhibitory effect of KIF15 knockdown on tumor growth. The mechanism study demonstrated the regulation of apoptosis‑ and cycle‑related proteins in the KIF15 KD‑induced inhibition of glioma. KIF15 was revealed to function as a tumor promoter in the development and progression of glioma. KIF15 also served as a prognostic indicator for glioma and may be a therapeutic target for glioma therapy.

The neutrophil-to-lymphocyte ratio (NLR) is an independent predictor of clinical outcome of different diseases, such as acute ischemic stroke, intracerebral hemorrhage, malignant tumor, and traumatic brain injury. However, the prognostic value of NLR plus admission Glasgow Coma Scale score (NLR-GCS) is still unclear in patients with diffuse axonal injury (DAI). Therefore this study assessed the relationship between the NLR-GCS and 6-month outcome of DAI patients. The clinical characteristics of DAI patients admitted to our department between January 2014 and January 2020 were retrospectively analyzed. The candidate risk factors were screened by using univariate analysis, and the independence of resultant risk factors was evaluated by the binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis. The predictive value of NLR-GCS in an unfavorable outcome was assessed by the receiver operating characteristics curve analysis. A total of 93 DAI patients were included. Binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis showed the level of NLR on admission was an independent risk factor of unfavorable outcomes in DAI patients. The ROC curve analysis showed that the predictive capacity of the combination of NLR and admission GCS score and combination of NLR and coma duration outperformed NLR, admission GCS score, and coma duration alone. The higher NLR level on admission is independently associated with unfavorable outcomes of DAI patients at 6 months. Furthermore, the combination of NLR and admission GCS score provides the superior predictive capacity to either NLR or GCS alone.