Interleukin 32 Increases Human Gastric Cancer cell invasion Associated with Tumor Progression and Metastasis
Menée in vivo, cette étude met en évidence des mécanismes par lesquels l'interleukine 32 favorise la formation de métastases pulmonaires d'un cancer de l'estomac
Purpose:The pro-inflammatory cytokine, interleukin 32 (IL-32), is a novel tumor marker highly expressed in various human carcinomas, including gastric cancer (GC). However, its effects on prognosis of GC patients and cancer metastasis are virtually unknown at present. The main aim of the current study was to explore the clinical significance of IL-32 in GC and further elucidate the molecular mechanisms underlying IL-32-mediated migration and invasion. Experimental Design:GC cells with ectopic expression or silencing of IL-32 were examined to identify downstream molecules and establish their effects on cell motility, invasion and lung metastasis in vivo. Results:IL-32 was significantly upregulated in GC and positively correlated with aggressiveness of cancer and poor prognosis. Ectopic expression of IL-32 induced elongated morphology and increased cell migration and invasion via induction of interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) expression via phospho AKT / phospho glycogen synthase kinase 3β (GSK3β) / active β-catenin as well as HIF-1α (hypoxia-inducible factors 1 alpha) signaling pathways. Conversely, Depletion of IL-32 in GC cells reversed these effects and decreased lung colonization in vivo. Examination of gene expression datasets in Oncomine and staining of GC specimens demonstrated the clinical significance of IL-32 and its downstream molecules by providing information on their co-expression patterns. Conclusions:IL-32 contributes to GC progression by increasing the metastatic potential resulting from AKT, β-catenin and HIF-1α activation. Our results clearly suggest that IL-32 is an important mediator for GC metastasis and independent prognostic predictor of GC.