Osteosarcoma (OS) presents diagnostic and treatment challenges due to its complexity and heterogeneity[22]. Recent advancements in tumor metabolism and gene therapy research have emphasized the significance of lactate metabolism-related genes (LMRGs) as valuable therapeutic targets[23–25]. In this study, we analyzed LMRGs and developed a risk profile model associated with overall survival in OS patients. Initially, we identified five LMRGs (MAGOHB, WAS, THUMPD1, MAP2K4, and NHLRC2) as prognostic indicators for OS using univariate Cox regression and LASSO regression. Subsequently, we constructed a risk model incorporating these LMRGs, which was validated through ROC curves, indicating its effectiveness in predicting OS patient survival. Additionally, we categorized OS into two distinct molecular subtypes based on LMRG expression. Furthermore, we developed a Nomogram prognostic model that combined risk scores with patients' clinical characteristics, demonstrating a strong predictive value for OS prognosis.
Barreiro et al. [26]reported that elevated MAGOH/MAGOHB expression in gliomas correlated with reduced overall survival and diminished treatment response. A pan-cancer analysis revealed overexpression of MAGOH/MAGOHB in 14 cancer types, including lung, breast, and bladder cancers, suggesting their widespread involvement in tumorigenesis. Zhou et al. [27] demonstrated significant up-regulation of MAGOH and MAGOHB in gastric cancer tissues. Simultaneous knockdown of MAGOH and MAGOHB in gastric cancer cells regulated CDK1, Cyclin B1, and p27 Kip1, inhibiting cell proliferation more effectively than individual treatments. However, in our study, high MAGOHB expression was associated with improved patient prognosis, contrary to their findings in other tumors. The underlying mechanism of MAGOHB in osteosarcoma development remains unclear, necessitating further investigation.
In the chromosome 17p region, two mitogen-activated protein kinase genes, MAP2K4 and MAPK7, are located[28]. The expression level of the MAP2K4 gene exhibited a strong correlation with clinical parameters in osteosarcoma. MAP2K4 overexpression was significantly associated with poor treatment response, tumor progression, and reduced overall survival, highlighting its pivotal role in osteosarcoma development and its potential as a marker for assessing treatment response and disease progression [29–31]. Our study also identified MAP2K4 as a protective gene associated with improved patient prognosis, consistent with previous research.
THUMPD1 plays a role in mRNA acetylation and n4-acetylcytidine production. It is highly expressed in various cancer types, with higher expression linked to better prognosis in renal cell carcinoma and rectal adenocarcinoma but poorer prognosis in hepatocellular carcinoma [32]. THUMPD1 is significantly associated with immune cell infiltration, tumor mutational load (TMB), microsatellite instability (MSI), immune checkpoints, and neoantigens across multiple cancer types. However, the role of THUMPD1 in osteosarcoma development and treatment outcomes remained unclear until our study, which found that higher THUMPD1 expression in osteosarcoma was associated with improved patient prognosis.
The NHLRC2 gene's function remains largely unknown, with two transcript variants in humans, both featuring six NHL repeats and the potential to form part of a TolB-like β-propeller protein, a common structural motif in various proteins. Mutations in NHLRC2 have been linked to fibrosis, central nervous system vascular abnormalities, and neurodegeneration[33–35]. NHLRC2 expression is higher in lung adenocarcinoma than in squamous cell carcinoma of the lung and is associated with shorter survival in lung adenocarcinoma patients[36]. NHLRC2 also plays a role in preventing reactive oxygen species (ROS)-induced cell death, but its relationship with osteosarcoma and its role in survival prognosis have not been previously reported. In our study, NHLRC2 acted as a risk factor affecting the survival of OS patients.
WAS, on the other hand, emerged as a protective factor for the prognosis of OS patients, although studies on the WAS gene's role in cancer have not been reported. Further research is needed to determine whether WAS can serve as a prognostic gene or therapeutic target in cancer. Additionally, the high expression of WAS in immune cells such as Mono/Macro, CD4 T+, and CD8T + cells in the single-cell dataset OS_GSE162454 suggests a potential role for immunotherapy in improving the prognosis of OS patients. Furthermore, the significant differences in immune and stromal scores between high and low-risk groups in the immune microenvironment score analysis support the potential for immunotherapy in OS treatment.
In summary, our study utilized bioinformatics approaches to construct a prognostic model for OS survival, highlighting the predictive value of LMRGs in OS prognosis. This research offers new potential therapeutic targets for OS prognosis and clinical management.