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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

01-12-2020 | Metastasis | Research

WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway

Authors: Dongmei Yang, Qing Li, Renduo Shang, Liwen Yao, Lianlian Wu, Mengjiao Zhang, Lihui Zhang, Ming Xu, Zihua Lu, Jie Zhou, Li Huang, Xiaodong Huang, Du Cheng, Yanning Yang, Honggang Yu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

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Abstract

Background

Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). However, the aberrant level of Wnt ligands in serum have not been explored. Here, we aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC.

Methods

The Oncomine database was used to analyze the relationship between WNT4 and the prognosis of CRC. ELISA was performed to measure WNT4 levels in serum and conditioned medium from fresh CRC tissues and adjacent normal tissues. Western blot and immunohistochemistry were carried out to measure the expression of WNT4 in human CRC tissues and adjacent normal tissues. The migration and invasion of CRC cells were determined by trans-well assay, and the effects of WNT4 on CRC invasion and metastasis in vivo were verified by tumor xenograft in nude mice. Cancer-associated fibroblasts (CAFs) and angiogenesis in subcutaneous nodules were detected by immunofluorescence (IF). In addition, the suspended spheres formation and tube formation assay were performed to explore the effects of WNT4 on CAFs and angiogenesis respectively.

Results

WNT4 was significantly upregulated in serum of CRC patients, and CRC tissues were identified as an important source of elevated WNT4 levels in CRC patients. Interestingly, elevated levels of WNT4 in serum were downregulated after tumor resection. Furthermore, we found that WNT4 contributed to epithelial-to-mesenchymal transition (EMT) and activated fibroblasts by activating the WNT4/β-catenin pathway in vitro and in vivo. Moreover, angiogenesis was induced via the WNT4/β-catenin/Ang2 pathway. Those effects could be reversed by ICG-001, a β-catenin/TCF inhibitor.

Conclusion

Our findings indicated that serum levels of WNT4 may be a potential biomarker for CRC. WNT4 secreted by colorectal cancer tissues promote the progression of CRC by inducing EMT, activate fibroblasts and promote angiogenesis through the canonical Wnt/β-catenin signalling pathway.
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Metadata
Title
WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway
Authors
Dongmei Yang
Qing Li
Renduo Shang
Liwen Yao
Lianlian Wu
Mengjiao Zhang
Lihui Zhang
Ming Xu
Zihua Lu
Jie Zhou
Li Huang
Xiaodong Huang
Du Cheng
Yanning Yang
Honggang Yu
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01774-w

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