Abstract
BACKGROUND: The small GTPase ADP-ribosylation factor 6 (ARF6) is key in cell membrane transport and cytoskeleton remodeling. It has been proven to drive the occurrence and development of a variety of tumors. The subject of this study is to investigate the expression characteristics, prognostic value, and mechanism of action of ARF6 in acute myeloid leukemia (AML). METHODS: We investigated ARF6 expression and prognostic significance using data from databases such as Genotype-Tissue Expression, The Cancer Genome Atlas Program, Gene Expression Omnibus database, and Cancer Cell Line Encyclopedia. Then we validated ARF6 expression in AML using clinical samples and cell lines. Subsequently, functional enrichment analysis of ARF6-related differential genes was carried out to explore the potential mechanism of ARF6 in the occurrence and development of AML. The expression level of ARF6 and its function and mechanism on AML cells were investigated by in vitro cell experiments. RESULTS: Our findings revealed that ARF6 was upregulated in most tumors compared with matched samples from healthy individuals, and its overexpression was significantly relevant to poor survival outcomes. In AML, ARF6 expression showed correlations with age, white blood cell count, French-American-British classification, and treatment outcomes. High ARF6 expression emerged as an independent prognostic factor in Cox regression analysis. Pathway enrichment analysis denoted that ARF6 mainly contributed to cell proliferation, cell adhesion, and immune regulation, and its expression level correlated with immune cell infiltration in AML. In addition, protein-protein interaction network analysis showed that ARF6 was associated with TLR4, ITGAX, ITGAM, FCGR3A, CD86, and CD4. Experimental validation demonstrated elevated ARF6 expression in AML patient samples, and the utilization of ARF6 inhibitors in AML cells resulted in the inhibition of cell proliferation, arrest of the cell cycle, and increase of apoptosis through the PI3K/AKT/NF-κB pathway. DISCUSSION: To sum up, our results suggest that high expression of ARF6 may serve as a potential marker for poor prognosis in AML by the PI3K/AKT/NF-κB pathway. This study provides novel insights into potential targeted therapies for AML, aiming to improve the prognosis of patients with this aggressive malignancy.