Abstract
Objective Forkhead box O 4 (FOXO4), a key albumen in the forkhead box O (FOXOs) family, plays crucial roles as a tumor suppressor in the cancer development. In our previous study, Peroxiredoxin1 (Prx1) promoted the development of oral cancer and was predicted to bind to FOXO4. The aim of this study was to investigate the clinicopathological significance of FOXO4 expression and its potential mechanism in head and neck squamous cell carcinomas (HNSCC). Methods The function of FOXO4 correlation with HNSCC prognosis was analyzed via ONCOMINE, UALCAN, Human Protein Atlas, and cBioPortal. The expression of FOXO4 was detected in Prx1 silenced CaL27 and SCC9 cell lines by Western blot. FOXO4 protein expression was observed via immunohistochemistry (IHC) and the binding of Prx1 to FOXO4 measured by Duolink analysis in a 4-nitro-quinoline-1-oxide- (4NQO-) induced tongue carcinogenesis model in Prx1+/+ and Prx1+/− mice. Results By the analysis of Bioinformation Databases, there was a significant interaction of FOXO4 down expression to clinical tumor stages and pathological grades in the patients with HNSCC. Reduced mRNA and protein expression of FOXO4 were found to be significantly correlated with the poor overall survival (OS) of HNSCC patients. FOXO4 expression is negatively related to Prx1 significantly in HNSCC tissues. By employing a 4NQO-induced oral carcinogenesis mouse model, we confirmed that FOXO4 expression was reduced in 4NQO-induced squamous cell carcinoma (SCC) tongue tissues compared with those in normal tissues. Prx1 knockdown resulted in the upregulation of FOXO4 expression in the SCC tissues and CaL27 and SCC9 cell lines. Furthermore, the interaction of Prx1 with FOXO4 was observed in mouse tongue tissues by Duolink analysis. Conclusion FOXO4 plays an important role in the development of HNSCC. The lower expression of FOXO4 is significantly correlated with the shorter OS in patients with HNSCC. FOXO4 is negatively regulated via interaction with Prx1. FOXO4 could be a potential molecular target for the treatment and prognosis of HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth malignancy with 700,000 new cases and 380,000 deaths rising annually globally
The transcriptional levels of Forkhead box O 4 (FOXO4) in HNSCC and normal samples were compared via ONCOMINE databases
The relationship between FOXO4 mRNA expression and clinicopathological parameters of patients with HNSCC were analyzed via UALCAN
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth malignancy with 700,000 new cases and 380,000 deaths rising annually globally. The 5-year overall survival (OS) rate of patients with oral cancer was less than 50% [1, 2]. The development of HNSCC is a complex and multistep process, which is affected by tumor biology and external stimulating factors. Studies have shown that the risk factors of HNSCC include tobacco, alcohol, betel nut, and human papillomavirus (HPV) [3, 4]. Several genes and signal pathways underlying the development of HNSCC have been explored. Patients with cyclooxygenase-2 (COX-2) overexpression suffered a worse overall survival rate [7]. It reported that the PI3K/AKT/PTEN pathway and COX-2 signaling pathway may contribute to early tumorigenesis and angiogenesis in Analytical Cellular Pathology
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