title: Hypoxia inducible factor 1α-mediated LOX expression correlates with migration and invasion in epithelial ovarian cancer.
abstract: This study investigated the role of LOX in promoting invasion and metastasis of epithelial ovarian cancer in a hypoxic environment and its specific signal transduction pathway. Immunohistochemical detection of HIF-1α and LOX protein expression was performed on formalin-fixed paraffin sections of normal ovary, benign ovarian tumors, borderline and malignant epithelial ovarian tumor paraffin sample, using Mann-Whitney U test for independent comparisons and Wilcoxon signed-ranks test for paired comparisons. HIF-1α and LOX were knocked down in epithelial ovarian cancer cells (EOC), and HIF-1α/LOX regulation mechanism and LOX catalytic activity under hypoxia/reoxygenation microenvironment were explored. Cell migration and invasion ability in LOX inhibited HO8910 cells were investigated under hypoxia/reoxygenation conditions, using matrigel cell invasion and migration assays. We found that HIF-1α and LOX are highly expressed in epithelial ovarian cancer tissues, and the expression of both proteins is significantly correlated with the tumor grade, tumor diameter and lymph node metastasis. HIF-1α expression is positively correlated with the expression of LOX. Specifically, the expression of LOX and HIF-1α markedly increases under hypoxic conditions and decreases after reoxygenation. siRNA knockdown of LOX or β-aminoproprionitrile (βAPN), an inhibitor of LOX activity, that attenuates LOX activity, downregulates HIF-1α protein expression and inhibits HO8910 migratory and invasive abilities. LOX catalytic activity is significantly reduced under hypoxic conditions. Moreover, EOC cells display a marked increase in LOX-dependent FAK/AKT activation and cell migration following hypoxia/reoxygenation. Collectively, our study demonstrates that the hypoxia-HIF-1α, LOX-FAK/AKT pathway regulates the migration and invasion of epithelial ovarian cancer cells under hypoxia/reoxygenation conditions, thus, promoting metastasis of ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Ji
authors.forename: You
authors.initials: Y
authors.lastname: Wang
authors.forename: Lihua
authors.initials: L
authors.lastname: Qiu
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.forename: Zhou
authors.initials: Z
authors.lastname: Liang
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wan
authors.forename: Wen
authors.initials: W
authors.lastname: Di
mesh_terms: D000328:Adult; D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008249:Protein-Lysine 6-Oxidase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt
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