Interleukin-32 increases human gastric cancer cell invasion associated with tumor progression and metastasis

Chung Ying Tsai, Chia Siu Wang, Ming Ming Tsai, Hsiang Cheng Chi, Wan Li Cheng, Yi Hsin Tseng, Cheng Yi Chen, Crystal D. Lin, Jun I. Wu, Lu Hai Wang, Kwang Huei Lin

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

Purpose: The proinflammatory cytokine interleukin-32 (IL-32) is a novel tumor marker highly expressed in various human carcinomas, including gastric cancer. However, its effects on prognosis of patients with gastric cancer and cancer metastasis are virtually unknown at present. The main aim of this study was to explore the clinical significance of IL-32 in gastric cancer and further elucidate the molecular mechanisms underlying IL-32-mediated migration and invasion. Experimental Design: Gastric cancer 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 gastric cancer 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 IL-8, VEGF, matrix metalloproteinase 2 (MMP2), and MMP9 expression via phosphor-AKT/phospho-glycogen synthase kinase 3β/active β-catenin as well as hypoxiainducible factor 1α (HIF-1α) signaling pathways. Conversely, depletion of IL-32 in gastric cancer cells reversed these effects and decreased lung colonization in vivo. Examination of gene expression datasets in oncomine and staining of gastric cancer specimens demonstrated the clinical significance of IL-32 and its downstream molecules by providing information on their coexpression patterns. Conclusions: IL-32 contributes to gastric cancer 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 gastric cancer metastasis and independent prognostic predictor of gastric cancer.

Original languageEnglish
Pages (from-to)2276-2288
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number9
DOIs
Publication statusPublished - 2014 May 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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