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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

Authors: Biao Geng, Jinshun Pan, Ting Zhao, Jie Ji, Chen Zhang, Ying Che, Jing Yang, Hui Shi, Juan Li, Hong Zhou, Xianmin Mu, Che Xu, Chao Wang, Yue Xu, Zheng Liu, Hao Wen, Qiang You

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Enzymatically inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. However, its role in gastric cancer (GC) tumorigenesis and metastasis has not yet been fully elucidated. We determined the significance of CHI3L1 expression in patients with GC. We also explored an as-yet unknown receptor of CHI3L1 and investigated the involved signaling in GC metastasis.

Methods

CHI3L1 expression was evaluated by immunoblotting, tissue microarray-based immunohistochemistry analysis (n = 100), and enzyme linked immunosorbent assay (ELISA) (n = 150). The interactions between CD44 and CHI3L1 or Interleukin-13 receptor alpha 2 (IL-13Rα2) were analyzed by co-immunoprecipitation, immunofluorescence co-localization assay, ELISA, and bio-layer interferometry. The roles of CHI3L1/CD44 axis in GC metastasis were investigated in GC cell lines and experimental animal model by gain and loss of function.

Results

CHI3L1 upregulation occurred during GC development, and positively correlated with GC invasion depth, lymph node status, and tumor staging. Mechanically, CHI3L1 binding to CD44 activated Erk and Akt, along with β-catenin signaling by phosphorylating β-catenin at Ser552 and Ser675. CD44 also interacted with IL-13Rα2 to form a complex. Notably, CD44v3 peptide and protein, but not CD44v6 peptide or CD44s protein, bound to both CHI3L1 and IL-13Rα2. Our in vivo and in vitro data further demonstrated that CHI3L1 promoted GC cell proliferation, migration, and metastasis.

Conclusions

CHI3L1 binding to CD44v3 activates Erk, Akt, and β-catenin signaling, therefore enhances GC metastasis. CHI3L1 expression is a novel biomarker for the prognosis of GC, and these findings have thus identified CHI3L1/CD44 axis as a vital pathway and potential therapeutic target in GC.
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Metadata
Title
Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer
Authors
Biao Geng
Jinshun Pan
Ting Zhao
Jie Ji
Chen Zhang
Ying Che
Jing Yang
Hui Shi
Juan Li
Hong Zhou
Xianmin Mu
Che Xu
Chao Wang
Yue Xu
Zheng Liu
Hao Wen
Qiang You
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0876-2

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