Identification of a novel FOXO3‑associated prognostic model in hepatocellular carcinoma.

Abstract

Although numerous molecular classifications are available to predict the prognosis of patients with hepatocellular carcinoma (HCC), they are still unsatisfactory. Forkhead box O3 (FOXO3) has been widely reported as a transcription factor involved in human cancers, but its role in HCC remains controversial. The present study aimed to explore the role of FOXO3 in HCC, as well as to identify biomarkers and construct prognostic models based on FOXO3. FOXO3 was highly expressed in HCC and was closely associated with poor prognosis in The Cancer Genome Atlas (the training set) and International Cancer Genome Consortium (the validation set). Subsequently, a co-expression network indicated that the red modules were closely related to FOXO3. Five key FOXO3-related genes [DEAD-box helicase 55 (DDX55), RAB10, member RAS oncogene family (RAB10), RAB7A, TATA-box binding protein associated factor, RNA polymerase I subunit B (TAF1B) and TAF3] were obtained using Cox-least absolute shrinkage and selection operator analyses. The 5-gene signature successfully predicted the prognosis of patients with HCC in both the training and validation sets. Enrichment analysis suggested marked differences in AKT and cell cycle-related (E2F targets and G₂/M checkpoints) pathways between HCC subgroups. Furthermore, the tumor microenvironment analysis suggested that the difference in the distribution of M2 macrophages among various subgroups may contribute to the poor prognosis using the CIBERSORTx framework. Furthermore, the mRNA and protein expressions of DDX55, RAB10, RAB7A, TAF1B and TAF3 were found to be higher in HCC tissues compared with paracancerous tissues using RT-qPCR and western blotting. Additionally, knockdown of RAB10, RAB7A and TAF3 inhibited proliferation of Huh7 cells, assessed by a Cell Counting Kit-8 assay. In conclusion, a novel FOXO3-related model was constructed and revealed that RAB10, RAB7A and TAF3 may be potential molecular targets or biomarkers for HCC.