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Published on: October 20, 2016
Cuproptosis-related Gene SLC31A1 Correlates with M2 Macrophage Infiltration and Serves as a Potential Therapeutic
Man Hu1, Yong Wang2, Yang Li1,3
1School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China.
Introduction:
Cuproptosis is a newly discovered form of programmed cell death that offers a new perspective on glioma treatment. However, the clinical impacts of CuproptosisRelated Genes (CRGs) in glioma remain largely unclear. This study aimed to investigate the role and biological significance of CRGs in glioma.
Methods:
The current study included 1573 glioma patients (603 from TCGA and 970 from the CGGA database) with clinicopathological information and mRNA sequencing data. The most relevant gene, SLC31A1, was identified among 16 CRGs through a series of approaches. Functional gene annotation was performed using GO, KEGG, and GSVA. Furthermore, correlations between CRGs and immune cell infiltration were analyzed by ESTIMATE and CIBERSORT algorithms. Single-cell RNA sequencing databases were used to verify the infiltration of M2 macrophages. Lastly, in vitro functional experiments were performed to assess the knockdown effects of SLC31A1 expression on the proliferation and invasion of glioma cells. Transcriptome sequencing of SLC31A1 knockdown cell lines was used to validate the functional enrichment analysis results. Mass spectrometry analysis was used to validate the protein-protein interactions. Immunofluorescence staining was used to co-localize the target protein with PD-L1, and the gene expression level was verified by immunohistochemistry.
Results:
Among the 16 CRGs, SLC31A1 was highly expressed and had the most important prognostic value. The expression of SLC31A1 increased with the degree of malignancy in glioma. SLC31A1 is an independent prognostic factor for gliomas, and an SLC31A1-based prognostic nomogram can reasonably predict the survival of patients. Functional enrichment analysis revealed that SLC31A1 co-expressed genes are mainly involved in immune and metabolismrelated signaling pathways. CIBERSORT analysis revealed that M2 macrophage cells increased with increasing SLC31A1 expression. SLC31A1 was closely associated with immune checkpoints PD-L1 and TIM3. Knockdown of SLC31A1 in glioma cells decreased cellular proliferation, migration, and invasion in vitro.
Discussion:
The strong correlation between SLC31A1 and M2 macrophage infiltration, coupled with its interaction with immune checkpoints, suggests that SLC31A1 mediates tumor progression by modulating the immunosuppressive microenvironment. These findings indicate that SLC31A1 is not only a copper transporter but also a key regulator of immune evasion in glioma.
Conclusion:
This study provides basic evidence that regulating cellular copper levels by targeting SLC31A1 is a feasible and patented therapeutic strategy. The high expression of SLC31A1 could promote the infiltration of M2 macrophages in glioma.
Insights
Cuproptosis-related gene SLC31A1 promotes glioma progression by increasing M2 macrophage infiltration and immune evasion. Targeting SLC31A1 offers a potential therapeutic strategy for glioma by regulating copper levels and the tumor microenvironment.
Area of Science:
- Oncology
- Cell Death Research
- Molecular Biology
Background:
- Cuproptosis, a novel programmed cell death pathway, presents new therapeutic avenues for glioma.
- The clinical significance of Cuproptosis-Related Genes (CRGs) in glioma remains largely unexplored.
- This study investigates the role and biological impact of CRGs in glioma pathogenesis.
Purpose of the Study:
- To identify key CRGs associated with glioma prognosis and progression.
- To elucidate the functional mechanisms of identified CRGs within the glioma microenvironment.
- To explore the potential of targeting CRGs as a therapeutic strategy for glioma.
Main Methods:
- Analysis of 1573 glioma patient samples (TCGA and CGGA) using mRNA sequencing.
- Identification of SLC31A1 as a key CRG through comprehensive analysis.
- Functional enrichment (GO, KEGG, GSVA), immune cell infiltration (ESTIMATE, CIBERSORT), and in vitro experiments (gene knockdown, cell proliferation, invasion assays).
Main Results:
- SLC31A1 was highly expressed in glioma, correlating with malignancy and serving as an independent prognostic factor.
- SLC31A1 expression positively correlated with M2 macrophage infiltration and immune checkpoints (PD-L1, TIM3).
- Knockdown of SLC31A1 reduced glioma cell proliferation, migration, and invasion, validating its role in tumor progression.
Conclusions:
- SLC31A1 promotes glioma progression by modulating the immunosuppressive microenvironment via M2 macrophage infiltration and immune checkpoint interactions.
- SLC31A1 functions as a key regulator of immune evasion in glioma, beyond its role as a copper transporter.
- Targeting SLC31A1 presents a feasible therapeutic strategy for glioma by modulating cellular copper levels and the immune microenvironment.