Abstract
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.
Highlights
Ovarian carcinoma, a commonly encountered primary malignancy, represents one of the deadliest malignant tumors in female patients around the world
Assessing the expression levels of these three proteins in tumor samples and normal specimens, we found that 62.9%, 60%, and 54.7% ovarian cancer tissue specimens were positive for Astrocyte-elevated gene1 (AEG-1), hypoxia-inducible factor- (HIF-)1α, and vascular endothelial growth factor (VEGF), respectively, for only 5%, 5%, and 10% obtained in normal ovarian tissue samples, respectively (Table 1)
We found that hypoxia associated upregulation of NF-κB, HIF-1α, and VEGF in SKOV3 cells was modulated by AEG-1
Summary
A commonly encountered primary malignancy, represents one of the deadliest malignant tumors in female patients around the world. Astrocyte-elevated gene (AEG-1) plays multiple roles and acts as an important molecule regulating a variety of events in carcinogenesis. Mounting evidence indicates that AEG-1 expression is elevated in a wide range of malignancies [1, 2], such as hepatocellular, gallbladder, renal cell, breast, lung, and ovarian carcinomas [3]. The mechanism by which AEG-1 regulates metastasis in ovarian carcinoma remains largely unknown. HIF-1α, firstly identified as a transcription factor, is activated by hypoxic stress. It acts as a hypoxiainducible nuclear factor in VSMCs and has significant functions in hypoxic responses in human cells, modulating the transcription of hypoxia-inducible genes [4]
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