title: Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility.
abstract: Human epididymis protein 4 (HE4) is a novel and specific biomarker for epithelial ovarian cancer (EOC). We previously demonstrated that serum HE4 levels were significantly elevated in the majority of EOC patients but not in subjects with benign disease or healthy controls. However, the precise mechanism of HE4 protein function is unknown. In this study, we generated HE4-overexpressing SKOV3 cells and found that stably transduced cells promoted cell adhesion and migration. Knockdown of HE4 expression was achieved by stable transfection of SKOV3 cells with a construct encoding a short hairpin DNA directed against the HE4 gene. Correspondingly, the proliferation and spreading ability of HE4-expressed cells were inhibited by HE4 suppression. Mechanistically, impaired EGFR and Erk1/2 phosphorylation were observed in cells with HE4 knockdown. The phosphorylation was restored when the knockdown cells were cultured in conditioned medium containing HE4. Moreover, in vivo tumorigenicity showed that HE4 suppression markedly inhibited the growth of tumors. This suggests that expression of HE4 is associated with cancer cell adhesion, migration and tumor growth, which can be related to its effects on the EGFR-MAPK signaling pathway. Our results provide evidence of the cellular and molecular mechanisms that may underlie the motility-promoting role of HE4 in EOC progression. The role of HE4 as a target for gene-based therapy might be considered in future studies.
authors.affiliation: Department of Clinical Laboratory, Fudan University, Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Renquan
authors.initials: R
authors.lastname: Lu
authors.forename: Xinghui
authors.initials: X
authors.lastname: Sun
authors.forename: Ran
authors.initials: R
authors.lastname: Xiao
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases