Diagnostic Value And Mechanism Of RNA M~6A Methylation Regulator YTHDF3 In Pan-cancer

Objective:N6-methyladenosine(m~6A)is the most abundant and extensive chemical modification of mammalian RNA molecules.Although numerous studies have investigated m~6A methylation-related genes,to the best of our knowledge,none have examined the expression patterns of YTH N6-methyladenosine RNA binding protein 3(YTHDF3)across cancers.Method:Using various publicly available datasets,we searched for a potential carcinogenic role of YTHDF3 in 33 tumor types.Furthermore,the clinicopathological parameters,clinical prognostic value,enrichment analysis,mutations,microsatellite instability(MSI),tumor mutation burden(TMB),levels of infiltrating cells,and related immune checkpoint genes were included.Finally,we performed a validation analysis using existing clinical samples and proliferation-related functional experiments.Results:YTHDF3 is highly expressed in most cancer types and associated with patient prognosis in certain tumors.The ROC analysis suggested that YTHDF3 has high diagnostic value in pan-cancer.Furthermore,we found that the genes associated with YTHDF3 were enriched for translation initiation and m RNA metabolic processes.The results of the GSEA enrichment suggest that YTHDF3 may be associated with different pathways in cells in various tumor types.We further analyzed the correlations between YTHDF3 expression and MSI,TMB,and immune checkpoint genes.YTHDF3 also possibly exerts important antitumor immunotherapy effects.Additionally,the results of the immune analysis using TIMER showed that high YTHDF3 expression levels in pan-cancer tissues were related to an immunosuppressive microenvironment.Finally,we experimentally demonstrated that both overexpression and downregulation of YTHDF3can affect cancer cell proliferation rates.In addition,our ROC curve showed that the target gene of YTHDF3,GLP2R,and its family gene,GLP1R,had the diagnostic value both individually and jointly in non-small cell lung cancer,and the proliferative effect of YTHDF3 may depend on GLP2R.Moreover,YTHDF3-mediated GLP2R regulation is dependent on m~6A modification.Conclusion:YTHDF3 is a promising biomarker for cancer diagnosis.This study provides the first comprehensive pan-cancer report on YTHDF3 and increases our understanding of its oncogenic role in different tumors.Figure[39]Table[20]Reference[47]...