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: Fang Ji, You Wang, Lihua Qiu, Shu Li, Jing Zhu, Zhou Liang, Yinsheng Wan, Wen Di
• Journal: International journal of oncology (Int J Oncol) Vol. 42 Issue 5 Pg. 1578-88 (May 2013) ISSN: 1791-2423 [Electronic] Greece
• PMID: 23545606 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Protein-Lysine 6-Oxidase
• Focal Adhesion Kinase 1
• PTK2 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Adult
• Aged
• Carcinoma, Ovarian Epithelial
• Cell Hypoxia (genetics)
• Cell Line, Tumor
• Cell Movement
• Female
• Focal Adhesion Kinase 1 (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Middle Aged
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis (genetics)
• Neoplasm Staging
• Neoplasms, Glandular and Epithelial (genetics, pathology)
• Ovarian Neoplasms (genetics, pathology)
• Protein-Lysine 6-Oxidase (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)