PRMT1 promotes radiotherapy resistance in glioma stem cells by inhibiting ferroptosis.

PURPOSE: The existence of glioma stem cells (GSCs) in cancer is related to glioma radiotherapy resistance. In this research, the effect of protein arginine methyltransferase 1 (PRMT1) on the radiosensitivity of glioma stem cell (GSC)-like cells, as well as its underlying mechanism, was investigated. METHODS: GSCs-like cells were analyzed and identified by flow cytometry. The self-renewal capability was evaluated by sphere-forming assay. The PRMT1 expression level in glioblastoma were analyzed using the Gene Expression Profiling Interactive Analysis database. The mRNA and protein were scrutinized by RT-qPCR and western blot, respectively. The radiosensitivity was evaluated by clonogenic survival assay. Ferroptosis was evaluated by detecting the levels of reactive oxygen species, malondialdehyde, Fe2+, glutathione, and 4-hydroxynonenal. RESULTS: U87 and SHG44 cells with GSC-like phenotype (GSC-U87 and GSC-SHG44) displayed strong expression of CD133 and nestin versus the glioma cells. GSC-U87 and GSC-SHG44 possess the self-renewal capability. The level of PRMT1 was higher in glioblastoma tumor tissues than in the normal paracancer tissues. Knockdown of PRMT1 enhanced the radiotherapy sensitivity of GSCs-like cells, which was evidenced by reduced survival fraction in GSC-U87 and GSC-SHG44 underwent sh-PRMT1 transfection. But, this effect was attenuated by Fer-1 (a ferroptosis inhibitor) treatment, accompanied by the abatement of ferroptosis. CONCLUSION: PRMT1 promoted radiotherapy resistance in GSCs-like cells by inhibiting ferroptosis.

Neuropilin-1 enhances temozolomide resistance in glioblastoma via the STAT1/p53/p21 axis.

Glioblastoma (GBM) is the most prevalent primary intracranial tumor. Temozolomide (TMZ) is the first-line chemotherapy for GBM. Nonetheless, the development of TMZ resistance has become a main cause of treatment failure in GBM patients. Evidence suggests that neuropilin-1 (NRP-1) silencing can attenuate GBM cell resistance to TMZ. This study aims to determine potential mechanisms by which NRP-1 affects TMZ resistance in GBM. The parental U251 and LN229 GBM cells were exposed to increasing concentrations of TMZ to construct TMZ-resistant GBM cells (U251/TMZ, LN229/TMZ). BALB/c nude mice were injected with U251/TMZ cells to establish the xenograft mouse model. Functional experiments were carried out to examine NRP-1 functions. Western blotting and real-time quantitative polymerase chain reaction were used to evaluate molecular protein and mRNA expression, respectively. Immunohistochemical staining showed NRP-1 and STAT1 expression in mouse tumors. The results showed that NRP-1 was highly expressed in TMZ-resistant cells. Moreover, knocking down NRP-1 attenuated the TMZ resistance of U251/TMZ cells, while upregulating NRP-1 enhanced TMZ resistance of the parental cells. NRP-1 silencing elevated GBM cell sensitivity to TMZ in tumor-bearing mice. Depleting NRP-1 reduced STAT1, p53, and p21 expression in U251/TMZ cells. STAT1 depletion offset NRP-1 silencing evoked attenuation of GBM cell resistance to TMZ. Collectively, our study reveals that NRP-1 enhances TMZ resistance in GBM possibly by regulating the STAT1/p53/p21 axis.

Dynamic Neuroimaging Biomarkers of Smoking in Young Smokers.

OBJECTIVE: To examine potential changes in the dynamic characteristics of regional neural activity in young smokers and to detect whether the changes were associated with smoking behavior. METHODS: The dynamic regional homogeneity (dReHo) and dynamic amplitude of low-frequency fluctuations (dALFF) in 40 young smokers and 42 nonsmokers were compared. Correlation analyses were also performed between dReHo and dALFF in areas showing group differences and smoking behavior [e.g., the Fagerström Test for Nicotine dependence (FTND) scores and pack-years]. RESULTS: Significantly differences in dReHo variability were observed in the inferior frontal gyrus (IFG), superior frontal gyrus (SFG), medial frontal gyrus (MFG), insula, cuneus, postcentral gyrus, inferior semi-lunar lobule, orbitofrontal gyrus, and inferior temporal gyrus (ITG). Young smokers also showed significantly increased dALFF variability in the anterior cingulate cortex (ACC) and ITG. Furthermore, a significant positive correlation was found between dALFF variability in the ACC and the pack-years; whereas a significant negative correlation between dReHo variability in the IFG and the FTND scores was found in young smokers. CONCLUSION: The pattern of resting state regional neural activity variability was different between young smokers and nonsmokers. Dynamic regional indexes might be a novel neuroimaging biomarker of smoking behavior in young smokers.

A study on the correlation between STAT­1 and mutant p53 expression in glioma.

Glioma is the most common primary brain tumor in adults and the second most common malignant tumor in children. Aberrant expression of signal transducer and activator of transcription 1 (STAT­1) and p53 are known to affect the occurrence and progression of malignant tumors. The aim of the present study was to investigate the expression of STAT­1 and mutant p53 gene, as well as their correlation, in patients with glioma. The present study included 50 patients who underwent glioma resection at the First Affiliated Hospital of Inner Mongolia Medical University between December 2007 and December 2011, and 10 patients with acute cerebral contusion who underwent intracerebral hematoma removal at the same hospital between January 2013 and January 2014. The expression of STAT­1 and mutant p53 protein in patients with different grades of glioma was assessed by immunohistochemistry. Spearman's correlation coefficient was employed to examine the correlation between STAT­1 and the grade of glioma, and mutant p53 expression. The results demonstrated that the mean expression of STAT­1 in glioma was significantly lower compared with normal brain tissue (P<0.05). However, there was no significant difference in the STAT­1 positive expression rate between the two groups (χ2=1.38, P>0.05). The expression score (P<0.05) and positive expression rate (χ2=31.27, P<0.05) of mutant p53 in glioma was significantly higher compared with those in normal brain tissue. Statistical analysis revealed a negative correlation between STAT­1 expression and the grade of glioma (r=­0.767, P<0.05). In addition, mutant p53 expression was negatively correlated with STAT­1 expression in glioma (r=­0.876, P<0.05). The observed negative correlation between STAT­1 and the pathological grade of glioma suggested an association between STAT­1 and the occurrence and development of glioma, thus revealing the potential of STAT­1 as a diagnostic biomarker and therapeutic target for glioma.

Gamma Knife radiosurgery combined with stereotactic aspiration as an effective treatment method for large cystic brain metastases.

In the present study, the efficacy and clinical outcomes of stereotactic aspiration combined with the Gamma Knife radiosurgery (GKRS) method were evaluated retrospectively for patients with large cystic brain metastases. This combined method aims to decrease the tumor weight (volume) and increase the possible radiation dose. The present study involved 48 patients who were diagnosed with cystic metastatic brain tumors between January 2008 and December 2012 in the Department of Neurosurgery of Nanfang Hospital Southern Medical University (Guangzhou, China). Every patient underwent Leksell stereotactic frame, 1.5T magnetic resonance imaging (MRI)-guided stereotactic cyst aspiration and Leksell GKRS. Subsequent to the therapy, MRI was performed every 3 months. The results indicated that 48 cases were followed up for 24-72 months, with a mean follow-up duration of 36.2 months. Following treatment, 44 patients (91.7%) exhibited tumor control and 4 patients (8.3%) experienced progression of the local tumor. During this period, 35 patients (72.9%) succumbed, but only 2 (4.2%) of these succumbed to the brain metastases. The total local control rate was 91.7% and the median overall survival time of all patients was 19.5 months. The 1-year overall survival rate was 70.8% and the 2-year overall survival rate was 26.2%. In conclusion, these results indicated that the method of stereotactic cyst aspiration combined with GKRS was safe and effective for patients with large cystic brain metastases. This method is effective for patients whose condition is too weak for general anesthesia and in whom the tumors are positioned at eloquent areas. This method enables patients to avoid a craniotomy, and provides a good tumor control rate, survival time and quality of life.

Mediation of multiple pathways regulating cell proliferation, migration, and apoptosis in the human malignant glioma cell line U87MG via unphosphorylated STAT1: laboratory investigation.

OBJECT: Signal transducer and activator of transcription 1 (STAT1) is thought to be a tumor suppressor protein. The authors investigated the expression and role of STAT1 in glioblastoma. METHODS: Immunohistochemistry was used to detect the expression of STAT1 in glioblastoma and normal brain tissues. Reverse transcription-polymerase chain reaction and Western blot analysis were used to detect mRNA and protein expression levels of STAT1. Cell growth, proliferation, migration, apoptosis, and the expression of related genes and proteins (Bcl-2, Bax, cleaved caspase-3, caspase-9, p21, and proliferating cell nuclear antigen) were examined in vitro via cell counting kit-8, wound-healing, flow cytometry, Rhodamine B, TUNEL, and Western blot assays. RESULTS: Human glioblastoma had decreased expression of STAT1 proteins. Transfection of the U87MG cells with STAT1 plasmid in vitro demonstrated significant inhibition of cell growth and an increase in apoptotic cell death compared with cells transfected with vector or mock plasmids. These effects were associated with the upregulation of cleaved caspase-3, Bax, and p21 and the downregulation of Bcl-2 expression. CONCLUSIONS: The results of this study suggest that increased expression of STAT1 by transfection with STAT1 plasmid synergistically inhibits human U87MG glioblastoma cell growth in vitro.