title: Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer.
abstract: OBJECTIVE
  Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo-response against anti-cancer drugs and prognosis of epithelial ovarian cancer.
  
  
  METHODS
  HE4-depleted cells and HE4-overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H-score.
  
  
  RESULTS
  Knockdown of HE4 in OVCAR-3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell-growth-related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti-tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4-overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H-score > 4.
  
  
  CONCLUSIONS
  HE4 induces chemoresistance against anti-cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients.
authors.affiliation: Department of Obstetrics and Gynecology, Gachon University, Gil Medical Center, Incheon, Republic of Korea.
authors.forename: Seungho
authors.initials: S
authors.lastname: Lee
authors.affiliation: Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
authors.forename: Seowon
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Seoul, Republic of Korea.
authors.forename: Yookyung
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Pathology, Gachon University, Gil Medical Center, Incheon, Republic of Korea.
authors.forename: Donghae
authors.initials: D
authors.lastname: Chung
authors.affiliation: Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Nohhyun
authors.initials: N
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016019:Survival Analysis; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011506:Proteins; D012333:RNA, Messenger; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: chemotherapy; human epididymis protein 4; ovarian cancer; prognosis