AEG-1 Contributes to Metastasis in Hypoxia-Related Ovarian Cancer by Modulating the HIF-1alphaNF-kappaBVEGF Pathway

الملخص EN

Objective.

Ovarian carcinoma represents one of the deadliest malignancies among female cancer patients.

Astrocyte-elevated gene-1 (AEG-1) participates in the ontogenesis of multiple human malignant diseases.

Here we evaluated AEG-1, hypoxia-inducible factor- (HIF-) 1α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and vascular endothelial growth factor (VEGF) amounts in hypoxia induced ovarian carcinoma cells.

This study aimed to explore the mechanism by which AEG-1 regulates metastasis in hypoxia induced ovarian carcinoma.

Patients and Methods.

AEG-1, HIF-1α, and VEGF protein amounts were evaluated by immunohistochemistry in 40 and 170 normal ovary and ovarian cancer tissue specimens, respectively.

In addition, AEG-1, HIF-1α, NF-κB, and VEGF mRNA and protein levels were determined by reverse quantified RT-PCR and WB, respectively, at different time periods (0–24 h) in epithelial ovarian cancer (EOC) SKOV3 cells treated in a hypoxia incubator.

Furthermore, NF-κB and VEGF gene and protein expression levels in AEG-1 knockdown EOC cells were quantitated by RT-PCR and WB, respectively.

Results.

AEG-1, HIF-1α, and VEGF amounts were significantly elevated in EOC tissue samples compared with normal ovary specimens (p<0.001).

Positive expression of HIF-1α and AEG-1 was associated with higher metastatic rate (p<0.01), lower FIGO stage (p<0.001), and degree of differentiation (p<0.001).

Meanwhile, EOC SKOV3 cells grew upon exposure to hypoxia for 8 h (p<0.001); at this time point, AEG-1, HIF-1α, NF-κB, and VEGF amounts peaked (p<0.001), at both the gene and the protein levels.

After AEG-1 knockdown, HIF-1α, NF-κB, and VEGF amounts were significantly decreased in EOC SKOV3 cells, also under hypoxic conditions (p<0.01).

Conclusions.

As an independent prognostic factor, AEG-1 was found to be significantly associated with hypoxia in ovarian cancer by regulating the HIF-1alpha/NF-kappaB/VEGF pathway.

Therefore, AEG-1 may be useful in determining disease stage and prognosis in ovarian cancer.