Abstract
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. 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. 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 hypoxia-inducible 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. 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.
Highlights
Gastric cancer is the fourth most common cancer type worldwide and ranks second in terms of global cancerrelated mortality [1]
IL-32 was significantly upregulated in gastric cancer and positively correlated with aggressiveness of cancer and poor prognosis
IL-32 contributes to gastric cancer progression by increasing the metastatic potential resulting from AKT, b-catenin, and hypoxiainducible factor 1a (HIF-1a) activation
Summary
Gastric cancer is the fourth most common cancer type worldwide and ranks second in terms of global cancerrelated mortality [1]. In Taiwan, gastric cancer was recorded as the sixth leading cause of cancer-related deaths in 2010 [2]. The prognosis of gastric cancer is poor, and the key players in molecular pathogenesis are predomi-. Authors' Affiliations: 1Department of Biochemistry, College of Medicine; 2Department of Nursing, Chang-Gung University of Science and Technology; 3Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan; 4Department of General Surgery, Chang Gung Memorial Hospital at Chiayi; 5National Health Research Institute, Zhunan, Miaoli, Taiwan, Republic of China; and 6Pre-med Program, Pacific Union College, Angwin, California. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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