- Inflammation Mediators in Ovarian Cancer Spheroids
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Abstract:
- Epithelial ovarian cancer (EOC) is one of the most lethal gynaecologic cancers worldwide. Patients often present with late-stage metastatic EOC, characterized by the accumulation of malignant ascites fluid, containing aggregates of cancer cells called spheroids. These patients have a very low survival rate of 30%. As such, there is a huge need to find novel vulnerabilities in metastatic EOC cells that we can exploit for therapeutic benefit, and identify candidate genes which can be targeted to reduce tumour growth and metastasis. Through the use of transcriptome-wide Gene Set Enrichment Analysis (GSEA) of two EOC cell lines (OVCAR8, iOvCa147), we identified various inflammation-associated transcriptional signatures that were enriched in spheroids compared with standard adherent cells. Using nine representative genes, results from RT-qPCR analyses demonstrated that DEC1, TXNIP and KLF9 were upregulated in spheroid cells compared to adherent cells across five different EOC cell lines. Using DEC1, a transcription factor involved in circadian rhythm, as a candidate gene due to its consistent upregulation across EOC cell lines and expression fold change ranging from a 2.2 to 5.6 increase over adherent cells, siRNA-mediated knockdown experiments were performed to assess whether it has a functional importance in the viability of EOC spheroids. Reducing gene expression of DEC1 reduced spheroid formation and cell viability in suspension culture as compared to adherent cells where there was no effect. Our identification of novel genes coordinately-regulated and functionally implicated in inflammation responses in EOC spheroids may allow the identification of novel therapeutic targets or biomarkers for early screening in this devastating disease.
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