title: WNT5A is a key regulator of the epithelial-mesenchymal transition and cancer stem cell properties in human gastric carcinoma cells.
abstract: OBJECTIVE
  Direct interaction with cancer-associated fibroblasts triggers WNT5A expression in human gastric carcinoma (GC) cells. In this study, we performed gene transduction experiments to investigate the significance of WNT5A in the GC tumor microenvironment.
  
  
  METHODS
  Gene transduction (pWNT5A and shWNT5A) was performed in human GC-derived MKN-7 cells. Altered gene expression was examined by RT-PCR and cDNA microarray analysis. Immunohistochemical examination was carried out in human GC tissues.
  
  
  RESULTS
  Transduction of exogenous WNT5A expression into MKN-7 cells upregulated genes related to the epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), and the pWNT5A transfectant showed high tumorigenicity in vivo. These results were confirmed by knockdown experiments using a lentivirus expressing shWNT5A. A cDNA microarray analysis suggested that depletion of endogenous WNT5A downregulated genes involved in intracellular signaling, chemokine-cytokine interaction and focal adhesion. High levels of WNT5A expression were observed in 66% of GC cases, with significant correlation with histological type. Interestingly, in intestinal-type GCs, WNT5A expression was detected in the periphery of tumor nests.
  
  
  CONCLUSIONS
  WNT5A regulates the induction of EMT and the maintenance of CSC properties in MKN-7 cells. WNT5A may play an important role in constructing an advantageous tumor microenvironment for the progression and development of human GC.
authors.affiliation: Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kanzawa
authors.forename: Shuho
authors.initials: S
authors.lastname: Semba
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hara
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokozaki
mesh_terms: D000368:Aged; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein