Abstract
AimsAnti-angiotherapy (Bevacizumab) is currently regarded as a promising option for glioma patients who are resistant to temozolomide (TMZ) treatment. But ongoing clinical research failed to meet therapeutic expectations. This study aimed to explore the pivotal genetic feature responsible for TMZ and Bevacizumab resistance in glioma patients.MethodsWe downloaded the transcriptomic and methylation data of glioma patients from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases and grouped these patients into resistant and non-resistant groups based on their clinical profiles. Differentially expressed genes and pathways were identified and exhibited with software in R platform. A TMZ-resistant cell line was constructed for validating the expression change of the candidate gene, ITGA5. An ITGA5-overexpressing cell line was also constructed to investigate its biological function using the CCK8 assay, Western blot, periodic acid–Schiff (PAS) staining, and transcriptional sequencing.ResultsChange of the cell morphology and polarity was closely associated with TMZ mono-resistance and TMZ/Bevacizumab dual resistance in glioma patients. The expression level of ITGA5 was effective in determining drug resistance and the outcome of glioma patients, which is regulated by methylation on two distinct sites. ITGA5 was augmented in TMZ-resistant glioma cells, while overexpressing ITGA5 altered the cell-promoted TMZ resistance through enhancing vascular mimicry (VM) formation correspondingly.ConclusionsBoth the epigenetic and transcriptional levels of ITGA5 are effective in predicting TMZ and Bevacizumab resistance, indicating that ITGA5 may serve as a predictor of the treatment outcomes of glioma patients.
Highlights
Glioma is a highly aggressive primary brain tumor
The omics data and clinical information of low-grade glioma (LGG) and GBM samples were downloaded from the Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/) and the Chinese Glioma Genome Atlas (CGGA; http://www.cgga.org.cn/) databases, while those of healthy samples were downloaded from the Genotype-Tissue Expression (GTEx) portal [28]
A total of 167 patients who received TMZ treatment were included, classified into complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and recurrent groups according to their disease progression and clinicopathological characteristics after TMZ treatment (Figure 1A)
Summary
The annual incidence of glioma is about 3–6/100,000 people, with a median post-diagnostic survival time of 14.6 months. TMZ is an oral alkylating agent that methylates the guanine at N7 and O6 and adenine at O3 on genomic DNA to form a mismatch during cell replication, resulting in permanent breakage of the DNA chain and cell death, . Only about 45% of glioma patients had short-term response to TMZ treatment, while the 5-year survival rate after TMZ treatment was even less than 10% in glioma patients [2]. The O6-methylguanine methyltransferase (MGMT)-mediated DNA repair machine can debug the TMZ-induced genomic mismatch, while epigenetic silencing of MGMT restores sensitivity to TMZ, along with longer overall survival (OS) in patients showing MGMT methylation [3, 4]. There is no specific remedy for this complicated problem
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
