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SLC12A5 as a novel potential biomarker of glioblastoma multiforme

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Abstract

Background

Glioblastoma multiforme (GBM) is the most prevalent and malignant intracranial tumor with significant features of dismal prognosis and limited therapeutic solutions. Consequently, the present studies are committed to exploring potential biomarkers through bioinformatics analysis, which may serve as valuable prognostic predictors or novel therapeutic targets and provide new insights into the pathogenesis of GBM.

Methods

We filtered overlapping differentially expressed genes (DEGs) based on expression profilings from three GBM microarray datasets (GSE116520, GSE4290 and GSE68848) and combined RNA sequencing data from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. Hub genes were prioritized from DEGs after performing protein–protein interaction (PPI) network analysis and weighted gene co-expression network analysis (WGCNA). This was followed by survival analysis to identify potential biomarkers among hub genes. Ultimately, the distributions of gene expressions, genetic alterations, upstream regulatory mechanisms and enrichments of gene functions of the identified biomarkers were analysed on public databases. QRT-PCR, immunohistochemical staining and western blotting was also used to confirm the gene expression patterns in GBM and normal brain tissues. CCK-8 assay clarified the effects of the genes on GBM cells.

Results

A total of 322 common DEGs were determined and nine genes were subsequently considered as hub genes by the combination of PPI network analysis and WGCNA. Only SLC12A5 had prognostic significance, which was deficient in GBM whereas especially enriched in normal neural tissues. SLC12A5 overexpression would inhibit cell proliferation of U251MG. Genetic alterations of SLC12A5 were rarely seen in GBM patients, and there was no apparent association existed between SLC12A5 expression and DNA methylation. SLC12A5 was prominently involved in ion transport, synapse and neurotransmitter.

Conclusion

SLC12A5 shows promise to function as a novel effective biomarker for GBM and deserves further systematic research.

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Data availability

The web links of the related public datasets or databases are as follows: GSE116520: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116520; GSE4290: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE4290; GSE68848: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE68848; GEPIA: http://gepia.cancer-pku.cn/; STRING: http://string.embl.de/; CGGA: http://cgga.org.cn/; HPA: http://www.proteinatlas.org/; cBioportal: https://www.cbioportal.org/; NCBI: http://www.ncbi.nlm.nih.gov; JASPAR: https://jaspar.genereg.net/; Metascape: http://metascape.org/; GSEA: http://www.broad.mit.edu/gsea/; GeneMANIA: http://genemania.org/. All the accesses above are open. Other data are available upon request.

Abbreviations

GBM:

Glioblastoma multiforme

CALD1:

Caldesmon 1

TREM1:

Triggering receptor expressed on myeloid cells 1

TMZ:

Temozolomide

PLK2:

Polo like kinase 2

GEO:

Gene expression omnibus

DEG:

Differentially expressed gene

TCGA:

The cancer genome atlas

GTEx:

Genotype-tissue expression

PPI:

Protein–protein interaction

WGCNA:

Weighted gene co-expression network analysis

CGGA:

Chinese glioma genome atlas

FC:

Fold change

GEPIA:

Gene expression profiling interactive analysis

RNA:

Ribonucleic acid

STRING:

Search tool for the retrieval of interaction genes

MCODE:

Molecular complex detection

OS:

Overall survival

cDNA:

Complementary deoxyribonucleic acid

qRT-PCR:

Quantitative real-time polymerase chain reaction

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

IHC:

Immunohistochemical

CCK-8:

Cell counting Kit-8

HPA:

Human protein atlas

cBioportal:

CBio cancer genomics portal

GO:

Gene ontology

BP:

Biological process

CC:

Cellular component

MF:

Molecular function

KEGG:

Kyoto encyclopedia of genes and genomes

GSEA:

Gene set enrichment analysis

HR:

Hazard ratio

LGG:

Lower grade glioma

GPCR:

G Protein-coupled receptor

SLC12A5:

Solute carrier family 12 member 5

KCC2:

K( +)-Cl(−) cotransporter-2

GABA:

Gamma-aminobutyric acid

MECP2:

Methyl-CpG binding protein 2

REST:

RE1 silencing transcription factor

EGR4:

Early growth response 4

SOX18:

SRY-box transcription factor 18

PATZ1:

POZ/BTB and AT hook containing zinc finger 1

SP2:

Specific protein 2

ARNT2:

Aryl hydrocarbon receptor nuclear translocator 2

USF2:

Upstream stimulatory factor 2

UTR:

Untranslated region

TWIST1:

Twist family bHLH transcription factor 1

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Acknowledgements

The authors are grateful to Ting Tang and Hui Liang for their assistance in clinical specimen collection, but they may not qualify for authorship, which have been acknowledged with their permission.

Funding

This research was financially supported by the National Natural Science Foundation of China (No.81672503 and No.81702484).

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Authors and Affiliations

  1. Department of Neurosurgery, Ningbo First Hospital, Ningbo, Zhejiang, China

    Jiakai Chen

  2. Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China

    Handong Wang & Maoxing Fei

  3. Department of Neurosurgery, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu, China

    Chulei Deng

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Contributions

HW and JC conceived and designed the study. JC, CD and MF carried out experiments and took part in the data collection and analysis. JC wrote the original manuscript. HW reviewed and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Handong Wang.

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Our study complied with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Jinling Hospital (No.2017NZGKJ-086).

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Chen, J., Wang, H., Deng, C. et al. SLC12A5 as a novel potential biomarker of glioblastoma multiforme. Mol Biol Rep 50, 4285–4299 (2023). https://doi.org/10.1007/s11033-023-08371-y

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