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

Abstract

BackgroundEnzymatically 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.MethodsCHI3L1 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.ResultsCHI3L1 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.ConclusionsCHI3L1 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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0876-2) contains supplementary material, which is available to authorized users.

EYA4 inhibits hepatocellular carcinoma by repressing MYCBP by dephosphorylating β‐catenin at Ser552

“…β-Catenin is one of the core proteins in the Wnt signaling pathway, and it was shown that phosphorylation at Ser552 and Ser675 of β-catenin could activate the β-catenin mediated signaling pathway. [24][25][26] In this study, in EYA4 overexpressed cells and EYA4 KO cells, the total level of β-catenin and p675-β-catenin did not change, but the level of p552-β-catenin was decreased in EYA4 overexpressed cells and increased in EYA4 KO cells. To investigate whether p552-β-catenin can facilitate transcription of MYCBP, we established β-catenin overexpressed plasmids with (WT) or without S552A mutation, a negative phosphorylated mutation of β-catenin at Ser552.…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Further, adherens and tight junctions become impaired, resulting in a mesenchymal phenotype [12,[71][72][73]. Altered E-and N-cadherin levels and the following β-catenin activation promote the expression of many tumor-associated proteins, including cyclin D1, CD44, or c-MYC [54,[74][75][76][77][78][79]. A transformation of cell phenotype enhances the migratory properties,…”

Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease

“…Therefore, we examined CHI3L1 and NPTX2 protein levels and cellular expression in the FC, a region affected early by plaque pathology during the progression of AD. These proteins were compared with other glial neuroinflammatory markers such as microglial ionized calcium-binding adapter molecule 1 (Iba1), complement component 1q (C1q), TREM2, astrocytic glial fibrillary acidic protein (GFAP), and glial surface adhesion glycoprotein CD44, which interacts directly with CHI3L1 [47] and drives immune responses in the central nervous system [48]. These proteins were quantified using immunoblotting and immunohistochemistry or immunofluorescence techniques.…”