Comprehensive Analysis of the Predictive Value of Adenylate Cyclase 4 on Clinical Significance, Prognosis, and...

Adenylate cyclase 4 (ADCY4), a member of the adenylate cyclase family, is an enzyme responsible for catalyzing the synthesis of the secondary messenger cyclic adenosine monophosphate (cAMP). Emerging evidence suggests a potential link between ADCY4 expression and the prognosis as well as biological behaviors of specific malignancies. Nevertheless, a systematic investigation into the role of ADCY4 in pan-cancer prognosis and its regulatory influence on the tumor microenvironment remains insufficient.

This study employed the HPA and GEPIA 2.0 databases to access ADCY4 expression across various human cancers. Utilizing R programming, we analyzed the relationship between ADCY4 expression and clinical characteristics, immune regulatory genes, immune checkpoint molecules, tumor microenvironment (TME) composition, tumor mutational burden (TMB), microsatellite instability (MSI) and drug sensitivity. DNA methylation levels of ADCY4 in uterine corpus endometrial carcinoma (UCEC) tissues were quantified using MethylTarget assay. Furthermore, in vitro experiments were conducted to validate ADCY4 expression patterns and to investigate its functional impact on UCEC cell proliferation and migratory capacity.

Analysis of TCGA datasets revealed a widespread downregulation of ADCY4 expression in multiple cancer types compared to corresponding normal tissues. ADCY4 expression levels demonstrated significant association with patient's prognosis, the expression of immune regulatory genes and checkpoints, and the degree of immune cell infiltration. Enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), indicated that ADCY4-related genes are predominantly involved in the cAMP signaling pathway. In UCEC, high ADCY4 expression was significantly associated with improved overall survival (OS) and disease specific survival (DSS). ADCY4 was confirmed to be downregulated in both UCEC tissues and cell lines. The MethylTarget assay indicated hypermethylation of ADCY4 in UCEC tissues relative to normal controls. Functional assays demonstrated that modulating ADCY4 expression significantly influenced cell proliferation and migration.

Our collective findings suggest that ADCY4 holds promise as a potential prognostic biomarker and a novel target for cancer immunotherapy.