Glioma is the most common malignant tumor of the central nervous system with poor survival. Temozolomide (TMZ) is the first-line chemotherapy drug for initial and recurrent glioma treatment with a relatively good efficacy, which exerts its antitumor effects mainly through cell death induced by DNA double-strand breaks in the G1 and S phases. However, endogenous or acquired resistance to TMZ limits glioma patients’ clinical outcome and is also an important cause of glioma replase. MicroRNA-195 (miR-195) plays an important role in the regulation of G1-phase/S-phase transition, DNA damage repair, and apoptosis of tumor cells. We found that miR-195 expression was significantly decreased in TMZ-resistant glioma cells induced with TMZ and correlated to the resistance index negatively. Also, the exogenous expression of miR-195 reversed TMZ resistance and induced the apoptosis of TMZ-resistant glioblastoma cells. Further bioinformatics analysis showed cyclin E1 (CCNE1) was a potential target gene of miR-195. Knockdown of CCNE1 partially reversed the effect of decreased miR-195 on TMZ resistance. The data from The Cancer Genome Atlas – Cancer Genome further suggested that hsa-miR-195 could negatively regulate the expression of CCNE1 in glioma. In conclusion, miR-195 reverses the resistance to TMZ by targeting CCNE1 in glioma cells and it could act as a potential target for treatment in glioma with TMZ resistance.

BackgroundGliomas are the most lethal primary brain tumors and are still a major therapeutic challenge. Oncolytic virus therapy is a novel and effective means for glioma. However, little is known about gene expression changes during this process and their biological functions on glioma clinical characteristics and immunity.MethodsThe RNA-seq data after oncolytic virus EV-A71 infection on glioma cells were analyzed to screen significantly downregulated genes. Once ABCD3 was selected, The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Genotype-Tissue Expression (GTEx), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) data were used to analyze the relationship between ABCD3 expression and clinical characteristics in glioma. We also evaluated the influence of ABCD3 on the survival of glioma patients. CIBERSORT and Tumor Immune Estimation Resource (TIMER) were also used to investigate the correlation between ABCD3 and cancer immune infiltrates. Gene set enrichment analysis (GSEA) was performed to functionally annotate the potential functions or signaling pathways related to ABCD3 expression.ResultsABCD3 was among the top 5 downregulated genes in glioma cells after oncolytic virus EV-A71 infection and was significantly enriched in several GO categories. Both the mRNA and protein expression levels of ABCD3 were upregulated in glioma samples and associated with the prognosis and grades of glioma patients. The Kaplan–Meier (K-M) curve analysis revealed that patients with high ABCD3 expression had shorter disease-specific survival (DSS) and overall survival (OS) than those with low ABCD3 expression. Moreover, ABCD3 expression could affect the immune infiltration levels and diverse immune marker sets in glioma. A positive correlation was found between ABCD3 and macrophages and active dendritic cells in the microenvironment of both the GBM and LGG. Gene sets including the plk1 pathway, tyrobp causal network, ir-damage and cellular response, and interleukin-10 signaling showed significant differential enrichment in the high ABCD3 expression phenotype.ConclusionOur results suggested that ABCD3 could be a potential biomarker for glioma prognosis and immunotherapy response and also further enriched the theoretical and molecular mechanisms of oncolytic virus treatment for malignant gliomas.