Correlation between SNPs of PIK3CA, ERBB2 3'UTR, and their interactions with environmental factors and the risk of epithelial ovarian cancer.

OBJECTIVE: To study the correlation between SNPs at phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) rs9838117 site, erb-b2 receptor tyrosine kinase 2 (ERBB2) rs1058808 site, and their interactions with environmental factors and the epithelial ovarian cancer (EOC) risk. METHODS: Sanger sequencing was used to analyze the genotypes of PIK3CA rs9838117 and ERBB2 rs1058808 site in 587 patients with epithelial ovarian cancer (EOC). Multi-factor dimensionality reduction (MDR) was applied to analyze the interaction between PIK3CA rs9838117 and ERBB2 rs1058808 site and the clinical data. RESULTS: The risk of EOC in T allele carriers at PIK3CA rs9838117 was 1.95 times (95%CI: 1.55-2.46, P<0.01) that of G allele carriers. The risk of EOC in G allele carriers at ERBB2 rs1058808 was as 0.64 times (95%CI: 0.54-0.75, P <0.01) as the risk for C allele carriers. In the interaction model between clinical data, PIK3CA rs9838117 site and ERBB2 rs1058808 SNP site, EOC risk in high-risk combination was 3.10 times (95%CI: 1.49-6.46, P <0.01) that of low-risk combination. CONCLUSION: The SNPs at PIK3CA rs9838117 and ERBB2 rs1058808 loci were associated with the risk of EOC.

Celastrol inhibits migration and invasion through blocking the NF-κB pathway in ovarian cancer cells.

Metastatic ovarian cancer is a major clinical challenge with poor prognosis and high mortality. Celastrol is a natural compound that has exhibits antiproliferative activity; however, its effects on metastasis-related phenotypes in ovarian cancer models are unclear. In the current study, the anti-invasive activities and associated signaling pathways of celastrol were determined in ovarian cancer cells. Cell proliferation was tested by MTT assay. Cell migration was detected by wound healing and Transwell assays, while cell invasion was detected by a Matrigel-coated Transwell method. In addition, nuclear factor (NF)-κB and matrix metalloproteinase (MMP) expression was examined by western blotting, and MMP-2/-9 activities were determined by gelatin zymography. At sub-toxic concentrations (<0.5 µM), celastrol inhibited migration and invasion in a concentration-dependent manner in SKOV-3 and OVCAR-3 cells. At the molecular level, celastrol blocked the canonical NF-κB pathway by inhibiting IκBα phosphorylation, and preventing IκBα degradation and p65 accumulation. Furthermore, the expression and activity of the NF-κB target protein MMP-9, but not MMP-2, were inhibited by celastrol. Furthermore, celastrol showed no synergistic effect with MG132, an NF-κB inhibitor. In conclusion, celastrol exhibited significant anti-invasive activities in ovarian cancer cells. Such functions may be mediated via NF-κB pathway blockade. The results of this in vitro study strengthen the value of applying celastrol as a potential clinical intervention modality for delaying ovarian cancer metastasis. This, celastrol warrants further preclinical investigation.