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Background: Skin cutaneous melanoma (SKCM) is the most malignant tumor among skin cancers. Immunotherapy has shown a great role in the advantageous prognosis of SKCM. However, only a small percentage of people can benefit from immunotherapy. To date, there has been insufficient evidence to reveal the prognostic value of m6A in SKCM and its relationship with the infiltration of immune cells and the efficacy of immunotherapy. Methods: Here, we synthetically analyzed 23 m6A regulators from SKCM samples collected from the TCGA and GEO databases. We defined three m6A modification patterns and constructed m6A scores using principal component analysis (PCA). Results: We found significant differences in overall survival (OS) and immune infiltration between different m6A subclusters. Besides, m6A score was positively correlated with regulatory T-cell and helper T-cell content, which may account for the association of high m6A scores with superior prognosis. Multivariate Cox regression analysis revealed that the m6A score was an independent prognostic indicator. Moreover, patients with high m6A scores showed a better response to immunotherapy, and this result was further validated in two independent immunotherapy cohorts receiving anti-PD-1/PD-L1 therapy. Conclusion:The findings suggested the m6A score can screen suitable candidates for immunotherapy and can predict immunotherapy response. This analysis of different m6A patterns in a large sample of SKCM expanded our understanding of TME and provided new ideas for prognostic assessment and personalized immunotherapy strategies for SKCM patients.

BackgroundOsteoarthritis (OA) is a degenerative joint disease frequently diagnosed in the elderly and middle-aged population. However, its specific pathogenesis has not been clarified. This study aimed to identify biomarkers for OA diagnosis and elucidate their potential mechanisms for restoring OA-dysregulated autophagy and inhibiting chondrocyte apoptosis in vitro.Material and methodsTwo publicly available transcriptomic mRNA OA-related datasets (GSE10575 and GSE51588) were explored for biomarker identification by least absolute shrinkage and selection operator (LASSO) regression, weighted gene co-expression network analysis (WGCNA), and support vector machine recursive feature elimination (SVM-RFE). We applied the GSE32317 and GSE55457 cohorts to validate the markers’ efficacy for diagnosis. The connections of markers to chondrocyte autophagy and apoptosis in OA were also comprehensively explored in vitro using molecular biology approaches, including qRT-PCR and Western blot.ResultsWe identified 286 differentially expressed genes (DEGs). These DEGs were enriched in the ECM-receptor interaction and PI3K/AKT signaling pathway. After external cohort validation and protein-protein interaction (PPI) network construction, PDK1 was finally identified as a diagnostic marker for OA. The pharmacological properties of BX795-downregulated PDK1 expression inhibited LPS-induced chondrocyte inflammation and apoptosis and rescued OA-dysregulated autophagy. Additionally, the phosphorylation of the mediators associated with the MAPK and PI3K/AKT pathways was significantly downregulated, indicating the regulatory function of PDK1 in apoptosis and autophagy via MAPK and PI3K/AKT-associated signaling pathways in chondrocytes. A significantly positive association between the PDK1 expression and Neutrophils, Eosinophils, Plasma cells, and activated CD4 memory T cells, as well as an evident negative correlation between T cells follicular helper and CD4 naive T cells, were detected in the immune cell infiltration analysis.ConclusionsPDK1 can be used as a diagnostic marker for OA. Inhibition of its expression can rescue OA-dysregulated autophagy and inhibit apoptosis by reducing the phosphorylation of PI3K/AKT and MAPK signaling pathways.