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J Exp Clin Cancer Res. 2019 Jan 28;38(1):38. doi: 10.1186/s13046-019-1046-x.

Knockdown of FOXO3a induces epithelial-mesenchymal transition and promotes metastasis of pancreatic ductal adenocarcinoma by activation of the β-catenin/TCF4 pathway through SPRY2.

Li J1,2, Yang R1,2, Dong Y1,2, Chen M1,2, Wang Y3, Wang G4,5.

Author information

1
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China.
2
Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
3
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China. tongjisiyu@163.com.
4
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China. wanggp@hust.edu.cn.
5
Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China. wanggp@hust.edu.cn.

Abstract

BACKGROUND:

Early invasion and metastasis are responsible for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), and epithelial-to-mesenchymal transition (EMT) is recognized as a crucial biological progress in driving tumor invasion and metastasis. The transcription factor FOXO3a is inactivated in various types of solid cancers and the loss of FOXO3a is associated with EMT and tumor metastasis. In this study, we sought to explore whether SPRY2, a regulator of receptor tyrosine kinase (RTK) signaling, is involved in FOXO3a-mediated EMT and metastasis in PDAC.

METHODS:

Immunohistochemistry was performed in 130 paired PDAC tissues and paracarcinomatous pancreatic tissues. Cell proliferation and apoptosis were assessed by cell counting kit and flow cytometry, while cell migration and invasion were evaluated with wound healing and transwell assays. The changes in mRNA and protein levels were estimated by qRT-PCR and western blot. BALB/c nude mice xenograft model was established to evaluate tumorigenesis and metastasis in vivo.

RESULTS:

FOXO3a expression was remarkably reduced in PDAC tissues, and correlated with metastasis-associated clinicopathologic characteristics and poor prognosis in patients with PDAC. In addition to the promotion of proliferation and suppression of apoptosis, knockdown of FOXO3a or SPRY2 induced EMT and promoted the migration and invasion of PDAC cells via activation of the β-catenin/TCF4 pathway. Moreover, silencing of SPRY2 reversed the suppressor effects induced by FOXO3a overexpression on EMT-associated migration and invasion of PDAC cells, while blockade of β-catenin reversed the effects of SPRY2 loss. FOXO3a knockdown decreased SPRY2 protein stability, whereas SPRY2 knockdown enhanced β-catenin protein stability. In vivo, FOXO3a knockdown promoted the tumorigenic ability and metastasis of PDAC cells.

CONCLUSIONS:

Our study suggests that knockdown of FOXO3a induces EMT and promotes metastasis of PDAC by activation of the β-catenin/TCF4 pathway through SPRY2. Thus, FOXO3a may represent a candidate therapeutic target in PDAC.

KEYWORDS:

Epithelial-to-mesenchymal transition; FOXO3a; Pancreatic ductal adenocarcinoma; SPRY2; β-Catenin/TCF4 pathway

PMID:
30691517
PMCID:
PMC6350320
DOI:
10.1186/s13046-019-1046-x
[Indexed for MEDLINE]
Free PMC Article

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