Integrative transcriptomic and experimental analyses identifies SDF4 as an astrocyte-expressed regulator of glioma progression through PI3K-AKT signaling.

backgroundGlioma is an aggressive brain tumor with poor prognosis and high recurrence, which significantly affects patients' quality of life. Identifying new biomarkers and therapeutic targets is crucial for improving diagnosis and treatment. This study focuses on the SDF4 gene, which has been implicated in various cancers; however, its role in glioma remains underexplored due to limited research.

methodsTo comprehensively investigate the role of SDF4 in glioma, we integrated bulk, single-cell, and spatial transcriptomic analyses with experimental validation. This approach includes bioinformatics evaluations, RNA sequencing analysis, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, survival analyses, gene enrichment assessments, and in vitro experimental validation. Furthermore, we explored the relationship between SDF4 expression and specific clinical parameters such as tumor grade and patient prognosis. The expression levels of SDF4 in invasive glioma specimens were assessed through immunohistochemical techniques.

resultsOur investigation reveals that SDF4 is markedly upregulated in glioma and correlates with unfavorable prognostic outcomes. Through Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression and weighted gene co-expression network analysis (WGCNA), SDF4 was identified as a pivotal prognostic biomarker; elevated levels of SDF4 were significantly linked to decreased overall survival rates. Functional enrichment analyses indicate that SDF4 regulates the cell cycle, mediates apoptosis, and remodels the extracellular matrix. Furthermore, single-cell and spatial transcriptomic studies have pinpointed SDF4 expression specifically within astrocytes, underscoring its essential function within the tumor microenvironment. In vitro experiments demonstrated that silencing SDF4 reduces glioma cell proliferation and promotes apoptosis; this effect is primarily mediated through the PI3K-Akt signaling pathway, as silencing effectively curtails its activation. Moreover, a notable elevation in SDF4 protein levels was observed in glioma patients. These elevated levels were associated with genetic mutations such as IDH1 and TERT, as well as clinical features including World Health Organization (WHO) classification and the methylation status of MGMT.

conclusionOur research underscores the critical role of SDF4 in glioma progression, highlighting its potential as a strategic target for glioma management and as a prognostic marker. Additionally, these findings pave the way for novel therapeutic strategies.