FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis.

Yan Sun,Lin Wang,Xuan Tian,Puqing Han,Mingsong Li,Jinghao Wu,Xuehu Xu

doi:10.3389/fcell.2021.659731

Abstract

Objective: Adenomatous polyposis coli 2 (APC2) is a colorectal cancer (CRC) tumor-suppressor gene. The progression of several kinds of cancer is closely associated with Forkhead box O4 (FOXO4). However, the function of FOXO4 in CRC is unclear. This study focused on the role of FOXO4 and the relationship between FOXO4 and APC2 in CRC migration and metastasis.Methods: The expressions of FOXO4, APC2, and p(S37)-β-catenin were detected in CRC tissues by immunohistochemistry, and their correlation was analyzed using the Spearman coefficient. Chromatin immunoprecipitation was used to test whether FOXO4 binds and regulates APC2 as a transcription factor. Either FOXO4 overexpression or APC2 knockdown was performed in CRC cell lines. The roles of FOXO4 and APC2 were investigated in CRC migration and metastasis.Results: FOXO4 was downregulated in CRC tissues compared with normal tissues and positively correlated with APC2 and p(S37)-β-catenin. FOXO4 could combine the promoter region of APC2 to upregulate its expression and increase the phosphorylated degradation of β-catenin. Stemness genes (CD133, ABCG1, and SOX2) were inhibited by FOXO4 overexpression in SW620 and HCT116 cell lines. Overexpressed FOXO4 suppressed epithelial–mesenchymal transition and the migration of CRC cell lines and metastasis of HCT116 in both the spleen and liver of nude mice, which was reversed by APC2 knockdown.Conclusion: This research demonstrates that overexpressed FOXO4 inhibits the migration and metastasis of CRC cells by enhancing the APC2/β-catenin axis, suggesting that FOXO4 is a potential therapeutic target of CRC.

Highlights

Colorectal cancer (CRC) is one of the most common cancer types
The immunohistochemical results of Forkhead box O4 (FOXO4) and Adenomatous polyposis coli 2 (APC2) in tissues of 40 patients with CRC were evaluated, showing that FOXO4 was positively correlated with APC2 at the protein level in CRC (P = 0.0143) (Figure 1B)
To ensure the stability of the above results, we used more CRC tissues to detect the expression of FOXO4 and APC2

Summary

Introduction

Colorectal cancer (CRC) is one of the most common cancer types. It has the third highest mortality rate globally (Dekker et al, 2019). Adenomatous polyposis coli 2 (APC2) is the homolog gene of adenomatosis polyposis coli (APC). It plays an essential role in tumor suppression in several cancers (van Es et al, 1999; Beta et al, 2015; Ying et al, 2015). APC2 activates the Wnt/β-catenin pathway via participating in the formation of a multiprotein “destruction complex” (Nakagawa et al, 1998; Croy et al, 2016; Saito-Diaz et al, 2018). Abnormal activation of the Wnt/β-catenin pathway is vital for promoting epithelial–mesenchymal transition (EMT) and is widespread in many tumors, including CRC (Sebio et al, 2014)

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Results

Discussion

Conclusion