title: Human epididymis protein 4 in association with Annexin II promotes invasion and metastasis of ovarian cancer cells.
abstract: BACKGROUND
  The objective of the present study was to identify human epididymis protein 4 (HE4) interacting proteins and explore the mechanisms underlying their effect on ovarian cancer cell invasion and metastasis.
  
  
  METHODS
  HE4 interacting proteins were identified by mass spectrometry and validated by co-immunoprecipitation and pull-down assays. The scratch test, the Transwell assay and animal experiments were used to assess the invasive and metastatic abilities of ovarian cancer cells before and after transfection and HE4 protein treatment. HE4 and annexin II protein expression in epithelial ovarian tissues was detected by immunohistochemistry, and the relation between their expression levels was examined.
  
  
  RESULTS
  Annexin II was identified as an HE4 interacting protein. HE4 and annexin II binding interaction promoted ovarian cancer cell invasion and metastasis. HE4 and annexin II expression levels were significantly higher in malignant epithelial ovarian tissues than in benign and normal epithelial ovarian tissues, and they were higher in tissues with lymph node metastases than in those without. HE4 gene interference downregulated the expression of MAPK and the FOCAL adhesion signaling pathway-associated molecules MKNK2 and LAMB2, and HE4 protein supplementation reversed this effect.
  
  
  CONCLUSIONS
  The binding interaction between HE4 and annexin II activates the MAPK and FOCAL adhesion signaling pathways, promoting ovarian cancer cell invasion and metastasis.
authors.forename: Huiyu
authors.initials: H
authors.lastname: Zhuang
authors.forename: Mingzi
authors.initials: M
authors.lastname: Tan
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Liu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Hu
authors.forename: Dawo
authors.initials: D
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Liancheng
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, No, 36 Sanhao Street, Heping District, Shenyang, Liaoning Province 110004, P,R, China. linbei88@hotmail.com.
authors.forename: Bei
authors.initials: B
authors.lastname: Lin
mesh_terms: D017306:Annexin A2 / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007797:Laminin / Q000235:genetics; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D017306:Annexin A2; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; C058783:laminin beta2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases