Abstract
Background
Glioma is the main subtype of primary central nervous system (CNS) tumor with high malignancy and poor prognosis under current therapeutic approaches. Glycolysis and suppressive tumor microenvironment (TME) are key markers of glioma with great importance for aggressive features of glioma and inferior clinical outcomes. Hexokinase 3 (HK3) is an important rate-limiting enzyme in glycolysis, but its function in glioma remains unknown.
Methods
This study comprehensively assessed the expression distribution and immunological effect of HK3 via pan-cancer analysis based on datasets from Genotype Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA). Furthermore, it explored the malignant phenotype and genomic landscape between low-HK3 and high-HK3 expression groups in gliomas from Chinese Glioma Genome Atlas (CGGA) and TCGA. Moreover, data from the TIMER website predicted the relationship between macrophage infiltration and HK3 expression. Also, single-cell sequencing data were used to validate the relationship.
Results
For pan-cancer patients, HK3 was expressed in various cancers. The results showed that HK3 was highly expressed in gliomas and positively correlated with tumor-infiltrating immune cells (TIICs), immune checkpoints, immunomodulators, and chemokines. Meanwhile, HK3 expression was highest in normal immune cells and tissues. In gliomas, the expression of HK3 was found to be closely correlated with the malignant clinical characteristics and the infiltration of macrophages. Also, HK3 was proven to be positively associated with macrophage through single-cell sequencing data and immunohistochemistry techniques. Finally, it is predicted that samples with high HK3 expression are often malignant entities and also significant genomic aberrations of driver oncogenes.
Conclusions
This is the first comprehensive research to figure out the relationship between HK3 and TME characteristics in gliomas. HK3 is positively associated with macrophage infiltration and can induce the immunosuppressive TME and malignant phenotype of gliomas.
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Funding
This work was funded by the National High Level Hospital Clinical Research Funding (2022-PUMCH-A-019) and Beijing Municipal Natural Science Foundation (7202150) for Yu Wang, and by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-113), the Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program (2019ZLH101) and the Beijing Municipal Natural Science Foundation (19JCZDJC64200[Z]) for Wenbin Ma, and Beijing Municipal Administration of Hospitals Incubating Program (PX2023062) for Xingang Zhou.
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TYL and XGZ conceived and designed the experiments. TYL and XGZ performed the experiments and analyzed the data. YW and WBM contributed to the analysis tools. TYL and XGZ wrote the paper. All authors gave final approval of the manuscript.
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Liang, T., Zhou, X., Wang, Y. et al. Glioma hexokinase 3 positively correlates with malignancy and macrophage infiltration. Metab Brain Dis (2024). https://doi.org/10.1007/s11011-023-01333-0
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DOI: https://doi.org/10.1007/s11011-023-01333-0