title: Interleukin-32 increases human gastric cancer cell invasion associated with tumor progression and metastasis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 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.
  
  
  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.
authors.affiliation: Authors' Affiliations: Department of Biochemistry, College of Medicine; Department of Nursing, Chang-Gung University of Science and Technology; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan; Department of General Surgery, Chang Gung Memorial Hospital at Chiayi; National Health Research Institute, Zhunan, Miaoli, Taiwan, Republic of China; and Pre-med Program, Pacific Union College, Angwin, California.
authors.forename: Chung-Ying
authors.initials: CY
authors.lastname: Tsai
authors.forename: Chia-Siu
authors.initials: CS
authors.lastname: Wang
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Tsai
authors.forename: Hsiang-Cheng
authors.initials: HC
authors.lastname: Chi
authors.forename: Wan-Li
authors.initials: WL
authors.lastname: Cheng
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Tseng
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Crystal D
authors.initials: CD
authors.lastname: Lin
authors.forename: Jun-I
authors.initials: JI
authors.lastname: Wu
authors.forename: Lu-Hai
authors.initials: LH
authors.lastname: Wang
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C496971:IL32 protein, human; D016209:Interleukin-8; D007378:Interleukins; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9