Identification of SSBP1 as a ferroptosis-related biomarker of glioblastoma based on a novel mitochondria-related gene risk model and in vitro experiments

Abstract

Background Glioblastoma (GBM) is the most common primary malignant brain tumor that leads to lethality. Several studies have demonstrated that mitochondria play an important role in GBM and that mitochondria-related genes (MRGs) are potential therapeutic targets. However, the role of MRGs in GBM remains unclear. Methods Differential expression and univariate Cox regression analyses were combined to screen for prognostic differentially-expressed (DE)-MRGs in GBM. Based on LASSO Cox analysis, 12 DE-MRGs were selected to construct a risk score model. Survival, time dependent ROC, and stratified analyses were performed to evaluate the performance of this risk model. Mutation and functional enrichment analyses were performed to determine the potential mechanism of the risk score. Immune cell infiltration analysis was used to determine the association between the risk score and immune cell infiltration levels. CCK-8 and transwell assays were performed to evaluate cell proliferation and migration, respectively. Mitochondrial reactive oxygen species (ROS) levels and morphology were measured using a confocal laser scanning microscope. Genes and proteins expression levels were investigated by quantitative PCR and western blotting, respectively. Results We identified 21 prognostic DE-MRGs, of which 12 DE-MRGs were selected to construct a prognostic risk score model for GBM. This model presented excellent performance in predicting the prognosis of patients with GBM and acted as an independent predictive factor. Functional enrichment analysis revealed that the risk score was enriched in the inflammatory response, extracellular matrix, and pro-cancer-related and immune related pathways. Additionally, the risk score was significantly associated with gene mutations and immune cell infiltration in GBM. Single-stranded DNA-binding protein 1 (SSBP1) was considerably upregulated in GBM and associated with poor prognosis. Furthermore, SSBP1 knockdown inhibited GBM cell progression and migration. Mechanistically, SSBP1 knockdown resulted in mitochondrial dysfunction and increased ROS levels, which, in turn, increased temozolomide (TMZ) sensitivity in GBM cells by enhancing ferroptosis. Conclusion Our 12 DE-MRGs-based prognostic model can predict the GBM patients prognosis and 12 MRGs are potential targets for the treatment of GBM. SSBP1 was significantly upregulated in GBM and protected U87 cells from TMZ-induced ferroptosis, which could serve as a prognostic and therapeutic target/biomarker for GBM.

SSBP1 is a novel prognostic marker and promotes disease progression via p38MAPK signaling pathway in multiple myeloma

“…In the mitochondria, SSBP1 is required for regulating mitochondrial function, cell metabolism, and tumorigenesis. [11][12][13][14] Furthermore, SSBP1 mutations impaired mitochondrial DNA maintenance and replication, which was related to optic atrophy, foveopathy, autosomal dominant optic atrophy, and a complex optic atrophy disorder. [15][16][17][18] Recently, it has been reported that the suppression of SSBP1 may be a potential therapy for the treatment of podocyte ferroptosis in glomerular injury.…”

“…In the mitochondria, SSBP1 is required for regulating mitochondrial function, cell metabolism, and tumorigenesis 11–14 . Furthermore, SSBP1 mutations impaired mitochondrial DNA maintenance and replication, which was related to optic atrophy, foveopathy, autosomal dominant optic atrophy, and a complex optic atrophy disorder 15–18 .…”

“…According to Jiang et al, 12 SSBP1 has been identified as a novel metastasis suppressor by participating in the dysregulation of mitochondrial signaling of triple‐negative breast cancer cells. Su et al 13 found that SSBP1 knockdown resulted in mitochondrial dysfunction and increased ROS levels, and increased temozolomide sensitivity in glioblastoma cells by enhancing ferroptosis. Wang et al 24 revealed that SSBP1disrupted mitochondrial function and inducing apoptosis in osteosarcoma cells.…”

Cancer-associated fibroblasts-derived exosomal piR-35462 promotes the progression of oral squamous cell carcinoma via FTO/Twist1 pathway

“…Proliferation assessment utilized the Cell Counting Kit-8 (CCK-8) and EdU cell proliferation assays, following manufacturer guidelines [34,35] . Proliferation rates were monitored every 24 hours with a multiscanner autoreader (BioTek, VT, US) and a uorescence microscope (Nikon, Japan).…”

Role of mitochondria in the regulation of ferroptosis and disease

“…This, in turn, inhibits the progression and migration of glioblastoma (GBM) cells by enhancing ferroptosis. SSBP1 has been identified as a potential ferroptosis-associated biomarker for GBM ( 97 ).Ferroptosis regulated by mitochondria plays a crucial role in cancer progression ( 98 , 99 ). Recent studies have revealed that cGAS is localized to the outer mitochondrial membrane, where it interacts with dynein-associated protein 1 (DRP1) to promote DRP1 oligomerization.…”