The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis.
Oncogene
; 39(7): 1414-1428, 2020 02.
Article
en En
| MEDLINE
| ID: mdl-31659258
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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias Gástricas
/
Transducción de Señal
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Comunicación Celular
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Factor de Necrosis Tumoral alfa
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Interleucina-33
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Fibroblastos Asociados al Cáncer
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Proteína 1 Similar al Receptor de Interleucina-1
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2020
Tipo del documento:
Article