Dataset Information

The immune regulation of BCL3 in glioblastoma with mutated IDH1.

ABSTRACT:

Background

Glioblastoma in the brain is the most malignant solid tumor with a poor prognosis. Screening critical targets and exploring underlying mechanisms will be a benefit for diagnoses and treatment. IDH1 mutation (R132) was used to distinguish glioblastoma grade and predict prognosis as a significant marker. However, the manner of IDH1 mutation regulating glioblastoma development was still unclear.

Methods

To study the function of IDH1 mutation, multi-type sequencing data (transcriptome, methylation and copy number variation) from the GEO and TCGA database were analyzed using bioinformatics techniques. The biological functions of IDH1 mutation (R132) would be comprehensively evaluated from the regulatory networks, tumor immune microenvironment and clinical relevance. Then the analysis result would be validated by experimental techniques.

Results

Compared with adjacent tissues, IDH1 was up-regulated in glioblastoma, which also positively correlated with the malignant degree and a poor prognosis. To further study the mechanism of mutated IDH1 (R132) function, 5 correlated genes (FABP5, C1RL, MIR155HG, CSTA and BCL3) were identified by different expression gene screening, enrichment analysis and network construction successively. Among them, the BCL3 was a transcription factor that may induce IDH1expression. Through calculating the correlation coefficient, it was found that in IDH1^mut glioblastoma, the dendritic cell infiltration was reduced which may result in a better prognosis. In addition, the level of IDH1, FABP5, C1RL, MIR155HG, CSTA and BCL3 might also influence lymphocytes infiltration (eg. CD4+ T cell) and chemokine expression (CXCL family).

Conclusions

IDH1 may participate in pathological mechanisms of glioblastoma via expression alteration or gene mutation. Furthermore, IDH1 mutation might improve prognosis via suppressing the expression of FABP5, C1RL, MIR155HG, CSTA and BCL3. Meanwhile, it was identified that BCL3 might perform similar immunomodulatory functions with IDH1 as an upstream transcript factor.

SUBMITTER: Fan S

PROVIDER: S-EPMC9134951 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

The immune regulation of BCL3 in glioblastoma with mutated IDH1.

Fan Shibing S Wu Na N Chang Shichuan S Chen Long L Sun Xiaochuan X

Aging 20220429 9

<h4>Background</h4>Glioblastoma in the brain is the most malignant solid tumor with a poor prognosis. Screening critical targets and exploring underlying mechanisms will be a benefit for diagnoses and treatment. IDH1 mutation (R132) was used to distinguish glioblastoma grade and predict prognosis as a significant marker. However, the manner of IDH1 mutation regulating glioblastoma development was still unclear.<h4>Methods</h4>To study the function of IDH1 mutation, multi-type sequencing data (tr ...[more]

PMID: 35488886

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Project description:Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of α-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant tumors is observed. In ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both isoforms were profoundly downregulated at the mRNA and protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites, nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy. IMPLICATIONS: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme.

Dataset Information

The immune regulation of BCL3 in glioblastoma with mutated IDH1.

Background

Methods

Results

Conclusions

Publications

The immune regulation of BCL3 in glioblastoma with mutated IDH1.

Similar Datasets

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