Identification of a novel glioblastoma multiforme molecular subtype with poor prognosis and high immune infiltration based on oxidative stress-related genes.

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor with a poor prognosis. Reactive oxygen species that accumulate during tumorigenesis can cause oxidative stress (OS), which plays a crucial role in cancer cell survival. Clinical and transcriptome data of TCGA-GBM dataset from UCSC Xena database were analyzed. Consensus clustering analysis was conducted to identify OS-related molecular subtypes for GBM. The immune infiltrate level between subtypes were characterized by ESTIMATE algorithm. Differentially expressed genes (DEGs) between subtypes were screened by DESeq2 package. Two OS-related molecular subtypes of GBM were identified, and cluster 2 had poorer overall survival and higher immune infiltration levels than cluster 1. Enrichment analysis showed that 54 DEGs in cluster 2 were significantly enriched in cytokine/chemokine-related functions or pathways. Ten hub genes (CSF2, CSF3, CCL7, LCN2, CXCL6, MMP8, CCR8, TNFSF11, IL22RA2, and ORM1) were identified in GBM subtype 2 through protein-protein interaction network, most of which were positively correlated with immune factors and immune checkpoints. A total of 55 small molecule drugs obtained from drug gene interaction database (DGIdb) may have potential therapeutic effects in GBM subtype 2 patients. Our study identified 10 hub genes as potential therapeutic targets in GBM subtype 2 patients, who have poorer overall survival and higher immune infiltration levels. These findings could pave the way for new treatments for this aggressive form of brain cancer.

Overexpression of CD2/CD27 could inhibit the activation of nitrogen metabolism pathways and suppress M2 polarization of macrophages, thereby preventing brain metastasis of breast cancer.

OBJECTIVE: Our study aimed to reveal the possible molecular mechanisms of CD2 and CD27 in influencing the tumor microenvironment of breast cancer (BC) brain metastasis based on the TCGA (The Cancer Genome Atlas) and SRA (Sequence Read Archive) databases. METHODS: We calculated the proportions of tumor-infiltrating immune cells and the immune and stromal cell scores in 1222 BC samples from the TCGA-BRCA dataset, followed by identification of candidate DEGs. We further screened for BC brain metastasis-related DEGs in the BC brain metastasis dataset SUB12911144 from the SRA database. Finally, we established a mouse breast cancer brain metastasis model for in vivo validation. RESULTS: We further screened two immune-regulatory DEGs (CD2 and CD27). GSEA analysis showed that the downregulation of CD2 and CD27 expression was closely related to the activation of nitrogen metabolism pathways. CIBERSORT algorithm analysis showed a correlation between the expression of 16 types of tumor-infiltrating immune cells and CD2 and 19 types of tumor-infiltrating immune cells and CD27. In addition, CD2 and CD27 expression were negatively associated with the proportion of M2 macrophages. In vivo experimental results demonstrated that overexpression of CD2/CD27 could suppress the M2 polarization of macrophages and inhibit breast cancer brain metastasis. CONCLUSION: In the tumor microenvironment, overexpression of CD2/CD27 inhibited the activation of nitrogen metabolism pathways and suppressed M2 polarization of macrophages, thereby preventing brain metastasis of breast cancer.

Methyl-CpG Binding Protein 2 as a Potential Diagnostic and Prognostic Marker Facilitates Glioma Progression Through Activation of Wnt/ß-Catenin Pathway.

BACKGROUND: Glioma is the primary malignant tumor in the central nervous system and has high malignancy, mortality, and recurrence rates. Because of its heterogeneity and drug resistance, the blood-brain barrier, and other factors, the treatment of glioma has mainly been surgical resection combined with traditional radiotherapy and chemotherapy. However, the therapeutic effect has not been satisfactory. Methyl-CpG binding protein 2 (MeCP2) is an epigenetic regulator that has been reported to regulate the initiation and progression of glioma. However, the underlying mechanism in glioma has remained unclear. METHODS: The gene expression of MeCp2, miR-138-5p, the epithelial-mesenchymal transition, the apoptosis-related gene, and the Wnt/ß-Catenin pathway-related gene and proliferation were detected by reverse transcription-quantitative polymerase chain reaction or Western blot. The cell proliferation and apoptosis of the glioma cell was assessed using the CCK-8 assay and flow cytometry assay. The relationship between miR-138-5p and MeCp2 was measured using the dual luciferase reporter assay. The effect of MeCp2 in U87 cells was examined in a xenograft tumorigenesis model in vivo. RESULTS: In our study, we found that MeCP2 was upregulated in glioma tissues and cell lines and that MeCP2 knockdown repressed cell proliferation and epithelial-mesenchymal transition but boosted cell apoptosis in glioma. Furthermore, MeCP2 knockdown attenuated in vivo glioma growth in a mice model. Mechanistically, miR-138-5p hindered the expression of MeCP2 by target MeCP2 and then inactivated the Wnt/ß-catenin signaling pathway. In addition, subsequent rescue assays disclosed that miR-138-5p repressed the glioma malignant phenotype and MeCP2 overexpression reversed the inhibitory effect of miR-138-5p upregulation. Consistently, overexpression of MeCP2 elevated glioma development. However, inhibition of the Wnt/ß-catenin signaling pathway with XAV-939 rescued the facilitation effect by overexpressing miR-138-5p. CONCLUSIONS: Our results have revealed that miR-138-5p/MeCP2/Wnt/ß-catenin signaling might be a new target axis for glioma treatment strategies.

LINC01426 aggravates the malignant progression of glioma through miR-661/Mdm2 axis.

BACKGROUND: Long intergenic non-protein coding RNA 1426 (LINC01426) is up-regulated in glioma and functions as a tumor promoter. However, the role of LINC01426 in glioma required further exploration. Therefore, this article mainly studied the role and possible mechanism of LINC01426 in glioma. METHODS: The area under the receiver operating characteristic curve was used to determine the diagnostic value of LINC01426. The effect of LINC01426 on tumor growth was analyzed by tumorigenesis assay and immunohistochemical analysis. Bioinformatics analysis, dual-luciferase assay, RNA pull-down, Pearson test, and real-time quantitative PCR (RT-qPCR) were applied to verify the relationship between target genes. The expressions and effects of LINC01426, miR-661 and MDM2 proto-oncogene (Mdm2) in glioma were examined by bioinformatics analysis combined with molecular and functional experiments (RT-qRCR, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide, clone formation, BrdU, flow cytometry). The expressions of proliferation and apoptosis-related proteins were determined by Western blot. RESULTS: LINC01426, which was high-expressed in glioma and was related to poor prognosis, could be used as a diagnostic marker for glioma. SiLINC01426 inhibited the malignant phenotype of glioma cells in vitro and attenuated tumor growth and PCNA expression in vivo, while the effects of LINC01426 were the opposite. LINC01426 targeted and inversely correlated with miR-661, which was low-expressed in glioma. MiR-661 inhibitor evidently overturned the effect of siLINC01426 on biological functions, proliferation, and apoptosis-related proteins of glioma cells. Mdm2 bound to miR-661. Moreover, siMdm2 reversed the effects of miR-661 inhibitor on the biological characteristics and Mdm2/p53/p21 expression of glioma cells. CONCLUSION: LINC01426 aggravated the malignant progression of glioma through miR-661/Mdm2 axis.