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.
Highlights
Inactive chitinase-like protein Chitinase 3-like 1 (CHI3L1) drives inflammatory response and promotes tumor progression
Correlation analysis revealed that high expression of CHI3L1 in gastric cancer (GC) tissues was significantly associated with a more aggressive tumor phenotype (Table 1)
CHI3L1 activates Extracellular regulated kinase (Erk) and Akt signaling through CD44 As CD44 closely correlates with the oncogenesis and metastasis of various cancers, we explored the molecular mechanism of CHI3L1/CD44 signaling in GC cells
Summary
Inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. It has been shown that CHI3L1 plays a critical role in antipathogen, oxidant-induced, inflammation, repair and remodeling responses by regulating a variety of essential biologic processes including oxidant injury, apoptosis, pyroptosis, inflammasome activation, Th1/Th2 inflammatory balance, M2 macrophage differentiation, transforming growth factor β1 (TGF-β1) elaboration, dendritic cell accumulation and activation, and parenchymal scarring [3,4,5,6]. Accumulating evidence has demonstrated that CHI3L1 enhances the inflammatory response in the tumor microenvironment and promotes tumor progression [7]. While CHI3L1 is known to be overexpressed in GC, its significance in gastric cancer progression and metastasis is not fully elucidated. Little is known regarding the underlying mechanisms and key downstream targets of CHI3L1 in tumor metastasis
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