ITGA5 Predicts Dual-Drug Resistance to Temozolomide and Bevacizumab in Glioma

Chang

2022

Cancers

With a median survival time of 15 months, glioblastoma multiforme is one of the most aggressive primary brain cancers. The crucial roles played by the extracellular matrix (ECM) stiffness in glioma progression and treatment resistance have been reported in numerous studies. However, the association between ECM-stiffness-regulated genes and the prognosis of glioma patients remains to be explored. Thus, using bioinformatics analysis, we first identified 180 stiffness-dependent genes from an RNA-Seq dataset, and then evaluated their prognosis in The Cancer Genome Atlas (TCGA) glioma dataset. Our results showed that 11 stiffness-dependent genes common between low- and high-grade gliomas were prognostic. After validation using the Chinese Glioma Genome Atlas (CGGA) database, we further identified four stiffness-dependent prognostic genes: FN1, ITGA5, OSMR, and NGFR. In addition to high-grade glioma, overexpression of the four-gene signature also showed poor prognosis in low-grade glioma patients. Moreover, our analysis confirmed that the expression levels of stiffness-dependent prognostic genes in high-grade glioma were significantly higher than in low-grade glioma, suggesting that these genes were associated with glioma progression. Based on a pathophysiology-inspired approach, our findings illuminate the link between ECM stiffness and the prognosis of glioma patients and suggest a signature of four stiffness-dependent genes as potential therapeutic targets.

Section: Discussionmentioning

confidence: 99%

Identification of Prognostic Genes in Gliomas Based on Increased Microenvironment Stiffness

Chang

2022

Cancers

“…The TMZ‐resistant U87MG cell line (U87MG‐TMZ‐R) was constructed as mentioned in our previous research. 14 Total RNA of U87MG and U87MG‐TMZ‐R cells were extracted with Trizol reagent, for isolating poly(A)‐containing mRNA and noncoding RNA with beads bearing oligo(dT). Sequenced reads were trimmed for adaptor sequence and masked for low‐complexity or low‐quality sequences, then mapped to the hg19 whole genome using HISAT2.…”

Section: Methodsmentioning

confidence: 99%

“…The TMZ‐resistant U87MG cell line (U87MG‐TMZ‐R) was constructed as mentioned in our previous research 14 . Total RNA of U87MG and U87MG‐TMZ‐R cells were extracted with Trizol reagent, for isolating poly(A)‐containing mRNA and noncoding RNA with beads bearing oligo(dT).…”

Section: Methodsmentioning

confidence: 99%

Comprehensive analysis of HHV‐6 and HHV‐7‐related gene signature in prognosis and response to temozolomide of glioma

Journal of Medical Virology

Zhao

Liu

et al. 2022

Self Cite

Human herpesvirus (HHV)‐6 and HHV‐7 have been detected in central nervous system and glioma tissue, while their exact role in glioma remains uncertain. Omics profiles and clinical information were downloaded from public databases, including The Cancer Genome Atlas cohort for training set and the Chinese Glioma Genome Atlas cohorts for validation sets. Differentially expressed genes between HHV‐6 and HHV‐7 infected or noninfected glioma patients were screened for establishing the HHV‐6 and HHV‐7 infection (HI) model through Lasso regression analysis. Bioinformatics methods were used to analyze the correlation between HI scores and prognosis, metastasis in glioma patients. Predictable efficacy of HI in temozolomide‐resistance and HI‐related genetic signatures were also explored. The HI model was constructed as: Risk score = (0.014709*DIRAS3) + (0.029787*TEX26) + (0.223492*FBXO39) + (0.074951*MYBL1) + (0.060202*HILS1). The five gene signature showed good performance in predicting survival time for glioma patients, while higher HI score is correlated with malignant features. Moreover, DNA mismatch repair genes were augmented in glioma patients with higher HI score as well as nonresponse to temozolomide treatment, which was in parallel with the transcriptomic result of temozolomide‐resistant glioma cell. Targeting the five gene signature is beneficial for prognosis of glioma patients, especially in glioma patients underwent temozolomide treatment.

“…For example, astrocytes have been shown to increase GBM survival and resistance against TMZ in coculture condition as compared to monoculture condition 11–14 . ECs are an important component of the perivascular niche and are responsible for increased resistance of GBM cells against TMZ 15–17 . GBM stem cell‐like cells are a subpopulation of GBM cells that express stemness‐related markers like NESTIN, SOX2, CD133, NANOG, and OCT4, have been reported to have high self‐renewal, multilineage differentiation, and heightened resistance to therapeutic treatments 8,9 .…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] ECs are an important component of the perivascular niche and are responsible for increased resistance of GBM cells against TMZ. [15][16][17] GBM stem cell-like cells are a subpopulation of GBM cells that express stemness-related markers like NESTIN, SOX2, CD133, NANOG, and OCT4, have been reported to have high self-renewal, multilineage differentiation, and heightened resistance to therapeutic treatments. 8,9 These cells can also trans-differentiate into ECs and enhance the resistance to antiangiogenic therapy, thereby resulting in treatment failure in GBM.…”

mentioning

confidence: 99%

The impact of temozolomide and lonafarnib on the stemness marker expression of glioblastoma cells in multicellular spheroids

Nakod

Kondapaneni

Edney

et al. 2022

Biotechnology Progress

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis. The GBM microenvironment is highly heterogeneous and is composed of many cell types including astrocytes and endothelial cells (ECs) along with tumor cells, which are responsible for heightened resistance to standard chemotherapeutic drugs such as Temozolomide (TMZ). Here, we investigated how drug treatments impact stemness marker expression of GBM cells in multicellular tumor spheroid (MCTS) models. Co‐ and tri‐culture MCTS constructed using U87‐MG GBM cells, astrocytes, and/or ECs were cultured for 7 days. At Day 7, 5 μM lonafarnib (LNF), 100 μM TMZ, or combination of 5 μM LNF + 100 μM TMZ was added and the MCTS were cultured for an additional 48 h. We assessed the spheroid sizes and expression of stemness markers‐ NESTIN, SOX2, CD133, NANOG, and OCT4‐ through qRT‐PCR and immunostaining. Following 48 h treatment with LNF, TMZ or their combination (LNF + TMZ), the spheroid sizes decreased compared to the untreated control. We also observed that the expression of most of the stemness markers significantly increased in the LNF + TMZ treated condition as compared to the untreated condition. These results indicate that drug treatment can influence the stemness marker expression of GBM cells in MCTS models and these aspects must be considered while evaluating therapies. In future, by incorporating other relevant cell types, we can further our understanding of their crosstalk, eventually leading to the development of new therapeutic strategies.