Gliomas are among the most invasive and lethal primary malignant tumors, originating from neuroglial precursor cells. Due to their rapid proliferation and high recurrence rate, they are considered one of the most challenging brain tumors to treat[8, 26]. The presence of the blood-brain barrier (BBB) poses a significant challenge in drug delivery and reduces drug sensitivity, resulting in poor prognoses for most glioma patients. Therefore, exploring new and effective treatment methods to improve the survival rate of glioma patients is of paramount importance[27, 28]. Advances in the study of molecular mechanisms have opened more possibilities for epigenetic and immunotherapy treatments targeting gliomas. Immunotherapy, as a novel treatment approach that has gradually been validated in clinical settings, has become a highly valuable direction in cancer treatment. This includes strategies aimed at stimulating both the innate and adaptive immune systems of patients against gliomas and promoting an immune-mediated anti-glioma response[29]. Given its ability to penetrate the BBB, the therapeutic prospects of immunotherapy in GBMLGG are promising.
The role of programmed cell death mechanisms, including ferroptosis, cuproptosis, and autophagy, in the onset, progression, and prognosis of cancer has always been a focal point of research. This study initiates with an analysis of a new PCD mechanism, Disulfidptosis, and its impact on pan-cancer prognosis. Employing robust machine learning techniques, it attempts to establish a prognostic prediction model for GBMLGG. The results demonstrate that the model, constructed using seven target genes (ACTN4, IQGAP1, DSTN, MYH9, PDLIM1, FLNB, and ACTB), achieved commendable predictive performance in C-index, Kaplan-Meier (KM), and Receiver Operating Characteristic (ROC) assessments across three datasets from TCGA and CGGA. In the analysis of the correlation between Disulfidptosis-related genes and the infiltration scores of 64 types of immune cells, as well as 60 immune checkpoint-related genes, and their respective prognostic performance in GBMLGG patients, we identified significant correlations with 13 cell lines (Astrocytes, cDC, CLP, Eosinophils, Fibroblasts, Hepatocytes, Macrophages_M2, Megakaryocytes, Myocytes, Neurons, Pericytes, Smooth muscle, Th2 cells) and 19 immune checkpoint-related genes (CD276, VEGFA, ARG1, KIR2DL3, IDO1, SLAMF7, CD274, CD70, PRF1, CD40LG, ICOS, GZMA, TNFRSF4, TNFRSF18, CD80, IL2RA, CXCL10, CXCL9, BTN3A1) to the target genes. These findings were further validated through single-cell analysis, PCR analysis of glioma cell lines, immunohistochemical analysis, and Summary data-based Mendelian Randomization (SMR) analysis.
The expression of ACTN4 is significantly correlated with tumor grading, aiding in the differentiation between astrocytic and oligodendroglial cells[30]. ACTN4 promotes glioma progression by enhancing the NF-κB signaling pathway through the promotion of NF-κB subunit nuclear translocation[31, 32]. Related to movement and the cytoskeleton, ACTN4 regulates tumor cell invasion and migration. By genetically modifying bone marrow mesenchymal stem cells (BM-MSCs) to express tumor-suppressing factors specifically, it inhibits tumor progression[33]. In glioma cell lines, we found that ACTN4 RNA expression was significantly increased in U251, T98G, and LN-18, while it was notably decreased in U87. In the HPA database, ACTN4 expression levels were found to be higher in glioma tissues compared to normal brain tissues.
IQGAP1-siRNA inhibits the proliferation and metastasis of U251 and U373 glioma cell lines[34]. Compared to non-cancerous tissues, IQGAP1 is often elevated in glioma tissues, and its high expression is associated with worse tumor grading and overall survival rates in glioma patients. Additionally, the overexpression of IQGAP1 enhances the proliferation and migration capabilities of human glioma cells, whereas siRNA knockdown of IQGAP1 reduces the in vitro growth and migration ability of these cells[35]. TRIM56 promotes glioma cell migration and invasion through the IQGAP1-CDC42 signaling axis[36]. The restoration of miR-124a inhibits glioma cell proliferation and invasion by suppressing IQGAP1 and β-catenin[37].
DSTN (Destrin, Actin Depolymerizing Factor) is a Protein Coding gene. The product of this gene belongs to the actin-binding proteins ADF family. This family of proteins is responsible for enhancing the turnover rate of actin in vivo. This gene encodes the actin depolymerizing protein that severs actin filaments (F-actin) and binds to actin monomers (G-actin).
DSTN DSTN Hypomethylation Promotes Radiotherapy Resistance of Rectal Cancer by Activating the Wnt/β-Catenin Signaling Pathway[38]. DSTN enhances lung cancer malignancy through facilitating β-catenin nuclear translocation and inducing EMT[39].
The MYH9 gene encodes the heavy chain of non-muscle myosin IIA, a widely expressed cytoplasmic myosin that participates in a variety of processes requiring the generation of intracellular chemomechanical force and translocation of the actin cytoskeleton[40]. HMGA1 stimulates MYH9-dependent ubiquitination of GSK-3β via the PI3K/Akt/c-Jun signaling pathway, promoting malignant progression and chemoresistance in gliomas[41]. Apatinib inhibits glioma cell malignancy in a patient-derived orthotopic xenograft mouse model by targeting the THBS1/MYH9 axis[42].
PDLIM1, a member of the PDZ-LIM family, is a cytoskeletal protein and functions as a platform to form distinct protein complexes, thus participating in multiple physiological processes such as cytoskeleton regulation and synapse formation. Emerging evidence demonstrates that PDLIM1 is dysregulated in a variety of tumors and plays essential roles in tumor initiation and progression. PDLIM1 is a novel signaling adaptor for p75(NTR), interacting with p75(NTR) in glioma stem cells/tumor-initiating cells derived from patients with high invasiveness. The knockdown of PDLIM1 using shRNA in vitro and in vivo can completely abolish the p75(NTR)-mediated invasion[43].Compared to the U87 cell line, the expression level of PDLIM1 protein is higher in the U251 cell line, which is consistent with our PCR results[44]. PDLIM1 is overexpressed in the Tumor Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GSE4412, and GSE43378 datasets[45].
Filamins (FLNs) are large dimeric actin-binding proteins that regulate actin cytoskeleton remodeling. In addition, FLNs serve as scaffolds for signaling proteins, such as tyrosine kinases, GTPases, or phosphatases, as well as for adhesive receptors, such as integrins. Thus, they connect adhesive receptors to signaling pathways and to cytoskeleton. There are 3 isoforms of FLN (filamin a [FLNa], FLNb, FLNc) that originate from 3 homologous genes.
The tumor suppressor gene FLNB acts as a switch gene in glioblastoma stem cells, involved in the "ECM receptor interaction" and "focal adhesion" pathways. Its inhibition may lead to dysregulation of cell communication pathways, thereby promoting tumor progression and invasiveness[46].
Beta-actin (ACTB) has traditionally been regarded as an endogenous housekeeping gene and has been widely used as a reference gene/protein in quantifying expression levels in tumors. However, ACTB is closely associated with a variety of cancers and accumulating evidence indicates that ACTB is de-regulated in liver, melanoma, renal, colorectal, gastric, pancreatic, esophageal, lung, breast, prostate, ovarian cancers, leukemia and lymphoma. ACTB is generally found to be up-regulated in the majority of tumor cells and tissues. The abnormal expression and polymerization of ACTB and the resulting changes to the cytoskeleton are revealed to be associated with the invasiveness and metastasis of cancers. ACTB and SDHA Are Suitable Endogenous Reference Genes for Gene Expression Studies in Human Astrocytomas Using Quantitative RT-PCR [47].