A Pan-Cancer Analysis of Transcription Factor Forkhead Box O-3: FOXO3

Abstract Background: Although available cell - or animal- based evidence supports the relationship between transcription factor FOXO3 and cancers, so far, there has been no pan-cancer analysis of FOXO3. Methods: We thus first carry on a pan-cancer analysis of FOXO3 across multiple tumors via several online websites based on the datasets of TCGA, including statistical correlations of FOXO3 expression with clinical prognosis, protein phosphorylation, cancer-associated fibroblasts infiltration, tumor mutational burden, and relevant cellular pathway. Results: FOXO3 was usually as an anti-tumor gene in KIRC, BLCA, CESC, UVM, LUAD and BRCA cancers, while a higher level of FOXO3 may have a certain cancer-promoting effect. As FOXO3 usually played a cancer-promoting role in ERα- BRCA but in ERα+ BRCA played an anti-tumor role, which may be due to transcription factor ERα translocating FOXO3 to the cytoplasm to weaken the transcription activity of FOXO3. FOXO3 activates autophagy related genes through transcription to maintain the occurrence of basal autophagy when basal autophagy is inhibited. However, FOXO3 can also induce apoptosis through transcription of pro-apoptotic genes if autophagy inhibition persists. The expression of phosphorylated FOXO3 protein at different sites may also affect its transcriptional activity by changing its shuttle between nucleus and cytoplasm. Therefore, When we analyze the functions of FOXO3 in a specific type of cancer, we should combine with the expression of FOXO3, the alteration status of FOXO3, the overall phosphorylation status of FOXO3, the basic autophagy status, the expression levels of ERα, SIRT1, CBP, FKBP5, RERE and SMAD4, and cancer-associated fibroblasts subtype, even consider the KRAS mutation, P53 mutation or non-genetic factors which can influence the functions of cancer-associated fibroblasts in the specific type of cancer. Conclusions: Our first pan-cancer study has provided a relatively comprehensive understanding of the role of FOXO3 in different tumors, and will give some help and enlightenment to later researchers who study the role of FOXO3 in various cancers.