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. 2020 Apr;19(4):3181-3188.
doi: 10.3892/ol.2020.11430. Epub 2020 Mar 3.

High expression of FOXO3 is associated with poor prognosis in patients with hepatocellular carcinoma

Shu-Shu Song  1   2   3 , Jia-Fu Ying  2   3   4 , You-Ni Zhang  2   3 , Hong-Ying Pan  2 , Xiang-Lei He  2 , Zhi-Ming Hu  2   3   5 , Hui-Ju Wang  3 , Xiao-Bing Dou  1 , Xiao-Zhou Mou  1   2   3
Affiliations

High expression of FOXO3 is associated with poor prognosis in patients with hepatocellular carcinoma

Shu-Shu Song et al. Oncol Lett. 2020 Apr.

Abstract

The role of forkhead box O3 (FOXO3) as a tumor suppressor gene and its association with the human lifespan is well documented. However, several studies have indicated that high expression of FOXO3 is also significantly associated with tumorigenesis. The aim of the present study was to determine the clinical significance of FOXO3 in the development and prognosis of hepatocellular carcinoma (HCC). mRNA expression data of FOXO3 from The Cancer Genome Atlas database was analyzed through the UALCAN online tool to compare the expression of FOXO3 between HCC and normal liver tissues. Subsequently, the expression of FOXO3 at the protein level was investigated via immunohistochemical staining of 314 HCC and 150 non-cancerous liver tissue samples. The association between protein expression and clinicopathological parameters was analyzed using the χ2 test, and the effect of FOXO3 expression on survival was assessed via Kaplan-Meier analysis. The expression of FOXO3 mRNA was significantly higher in HCC in comparison with healthy tissues. High FOXO3 protein expression was revealed in 43/150 non-cancerous liver tissues, and in 238/314 HCC samples. A significant association was demonstrated between FOXO3 expression and metastasis, Tumor-Node-Metastasis stage, Edmondson grade, α-fetoprotein level and overall survival. In conclusion, the high expression of FOXO3 predicts a poor prognosis in patients with HCC, indicating this protein as a potential therapeutic target in HCC.

Keywords: forkhead box O3; hepatocellular carcinoma; prognosis.

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Figures

Figure 1.
Figure 1.
Expression of FOXO3 according to The Cancer Genome Atlas database. (A) Expression of FOXO3 in normal liver and HCC tissues. Association between FOXO3 expression and (B) clinical TNM staging of HCC, and (C) histological grade of HCC. ***P<0.001. FOXO3, forkhead box O3; HCC, hepatocellular carcinoma.
Figure 2.
Figure 2.
Results of FOXO3 immunohistochemistry. Staining of HCC tissues revealed (A) Strong expression; (B) moderate expression; and (C) no expression of FOXO3 in HCC tissues. Magnifications, ×40 and ×400. FOXO3, forkhead box O3.
Figure 3.
Figure 3.
Location of the FOXO3 gene in the mitochondrial gene transcription and its interaction genes. The functional enrichment analysis of genes interacting with FOXO3 revealed that the FOXO3 gene serves a key role in the transcription and regulation of genes. FOXO3, forkhead box O3.
Figure 4.
Figure 4.
Kaplan-Meier survival curves of patients with HCC with high or low FOXO3 expression. (A) Kaplan-Meier survival curves of patients recruited in the present study with HCC and high or low FOXO3 expression. (B) Kaplan-Meier analysis of TCGA dataset describing the effect of FOXO3 expression level on survival time of patients with HCC. The present results are consistent with TCGA database, the higher expression of FOXO3 in cancer tissues the survival rate was lower. HCC, hepatocellular carcinoma; FOXO3, forkhead box O3; TGCA, The Cancer Genome Atlas.
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