m6A-Related lncRNAs Predict Overall Survival of Patients and Regulate the Tumor Immune Microenvironment in Osteosarcoma

Abstract

Background. m6A-related lncRNAs have demonstrated great potential tumor diagnostic and therapeutic targets. The goal of this work was to find m6A-regulated lncRNAs in osteosarcoma patients. Method. The Cancer Genome Atlas (TCGA) database was used to retrieve RNA sequencing and medical information from osteosarcoma sufferers. The Pearson’s correlation test was used to identify the m6A-related lncRNAs. A risk model was built using univariate and multivariable Cox regression analysis. Kaplan–Meier survival analysis and receiver functional requirements were used to assess the risk model's performance (ROC). By using the CIBERSORT method, the associations between the relative risks and different immune cell infiltration were investigated. Lastly, the bioactivities of high-risk and low-risk subgroups were investigated using Gene Set Enrichment Analysis (GSEA). Result. A total of 531 m6A-related lncRNAs were obtained from TCGA. Seven lncRNAs have demonstrated prognostic values. A total of 88 OS patients were separated into cluster 1, cluster 2, and cluster 3. The overall survival rate of OS patients in cluster 3 was more favorable than that of those in cluster 1 and cluster 2. The average Stromal score was much higher in cluster 1 than in cluster 2 and cluster 3 ( P < 0.05 ). The expression levels of lncRNAs used in the construction of the risk prediction model in the high-risk group were generally lower than those in the low-risk group. Analysis of patient survival indicated that the survival of the low-risk group was higher than that of the high-risk group ( P < 0.0001 ) and the area under the curve (AUC) of the ROC curve was 0.719. Using the CIBERSORT algorithm, the results revealed that Macrophages M0, Macrophages M2, and T cells CD4 memory resting accounted for a large proportion of immune cell infiltration. By GSEA analysis, our results implied that the high-risk group was mainly involved in unfolded protein response, DNA repair signaling, and epithelial-mesenchymal transition signaling pathway and glycolysis pathway; meanwhile, the low-risk group was mainly involved in estrogen response early and KRAS signaling pathway. Conclusion. Our investigation showed that m6A-related lncRNAs remained tightly connected to the immunological microenvironment of osteosarcoma tumors, potentially influencing carcinogenesis and development. The immune microenvironment and immune-related biochemical pathways can be changed by regulating the transcription of M6A modulators or lncRNAs. In addition, we looked for risk-related signaling of m6A-related lncRNAs in osteosarcomas and built and validated the risk prediction system. The findings of our current analysis will facilitate the assessment of outcomes and the development of immunotherapies for sufferers of osteosarcomas.

Recent advances of m6A methylation in skeletal system disease

“…Such as, Chen et al reveled that hyper-methylated hsa_circ_0007259 activated STAT3 signaling pathway via sponge miR-21-5p and could be acted as a potential biomarker in RA [ 215 ]. Besides, it has been reported that m6A-related lncRNAs regulated the tumor immune microenvironment and predicted the overall survival of OS patients [ 190 , 216 ]. Although researchers have made progress in exploring the diagnosis value of m6A methylation in SSD, further detailed studies are needed to verify the effectiveness, accuracy and feasibility of these findings in larger samples.…”

m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism

“…Afterwards, high expression of PGK1 can promote glycolysis and proliferation of osteosarcoma cells [ 154 ]. Besides, Bi et al analyzed seven prognostic m6A related lncRNAs in osteosarcoma and found that they play an important role in the glycolysis process of osteosarcoma [ 155 ].…”

N6-methyladenosine (m6A) modification in osteosarcoma: expression, function and interaction with noncoding RNAs – an updated review

“…Moreover, LINC00538 was positively correlated with resting dendritic cells and negatively linked to activated dendritic cells in our results. m6A-associated lncRNAs are closely associated with the immune microenvironment of osteosarcoma tumours and may influence tumour occurrence and progression [ 80 ]. These findings reveal new directions in the role of m6A and lncRNA in the immune microenvironment of osteosarcoma and demonstrate that m6A modification may be a potential therapeutic target for anti-tumour immunotherapy.…”