title: Reactive oxygen species promote ovarian cancer progression via the HIF-1α/LOX/E-cadherin pathway.
abstract: Reactive oxygen species (ROS) can drive the de‑differentiation of tumor cells leading to the process of epithelial-to-mesenchymal transition (EMT) to enhance invasion and metastasis. The invasive and metastatic phenotype of malignant cells is often linked to loss of E-cadherin expression, a hallmark of EMT. Recent studies have demonstrated that hypoxic exposure causes HIF-1-dependent repression of E-cadherin. However, the mechanism by which ROS and/or HIF suppresses E-cadherin expression remains less clear. In the present study, we found that ROS accumulation in ovarian carcinoma cells upregulated HIF-1α expression and subsequent transcriptional induction of lysyl oxidase (LOX) which repressed E-cadherin. Loss of E-cadherin facilitated ovarian cancer (OC) cell migration in vitro and promoted tumor growth in vivo. E-cadherin immunoreactivity correlated with International Federation of Gynecology and Obstetrics (FIGO) stage, tumor differentiation and metastasis. Negative E-cadherin expression along with FIGO stage, tumor differentiation and metastasis significantly predicted for a lower 5-year survival rate. These findings suggest that ROS play an important role in the initiation of metastatic growth of OC cells and support a molecular pathway from ROS to aggressive transformation which involves upregulation of HIF-1α and its downstream target LOX to suppress E-cadherin expression leading to an increase in cell motility and invasiveness.
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Yueping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Medicine and UC San Diego Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
authors.affiliation: Department of Medicine and UC San Diego Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D008249:Protein-Lysine 6-Oxidase