Abstract
Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor–stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial–mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.
Highlights
These authors contributed : Quan Zhou, Xiongyan Wu
Using an in vitro model, we demonstrate that CAFsderived IL-33 promotes migration, invasion and epithelial–mesenchymal transition (EMT) of Gastric cancer (GC) cells by activation of the ERK1/2/SP1/ZEB2 pathway via ST2L, and that in turn, GC cell derived-TNF-α upregulates IL-33 expression in cancer-associated fibroblasts (CAFs) via the TNFR2/normal fibroblasts (NFs)-κB/interferon regulatory factor 1 (IRF-1) pathway
ST2L expression in epithelial cells positively correlated with IL-33 expression in stromal cells (r = 0.6503, P < 0.001) (Fig. 1c, e), which suggested that IL-33 and its receptor ST2L, while being expressed in different cell types, were coordinately overexpressed in the same GC tissues
Summary
Cancer-associated fibroblasts (CAFs), the activated fibroblasts in cancer stroma, have been shown to promote cancer progression by interacting with diverse cell types through the secretion of cytokines and local extracellular matrix (ECM) [14,15,16]. IL-33 has been found to mediate Th2 immune responses by binding and signaling through ST2L, an orphan receptor in the IL-1R family, to induce NF-κB and MAPK (p38, JNK and ERK1/2) activation, and promote Th2 cytokine production [19,20,21,22,23]. Using an in vitro model, we demonstrate that CAFsderived IL-33 promotes migration, invasion and epithelial–mesenchymal transition (EMT) of GC cells by activation of the ERK1/2/SP1/ZEB2 pathway via ST2L, and that in turn, GC cell derived-TNF-α upregulates IL-33 expression in CAFs via the TNFR2/NF-κB/IRF-1 pathway. We identify TNF-α/IL-33/ST2L signaling as a mediator of the tumor–stromal cell interaction in GC
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