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Metformin Affects the Transcriptomic Profile of Chicken Ovarian Cancer Cells
Lalitha Gopalan1, Aswathy Sebastian2, Craig A Praul2
1Department of Animal Science, The Pennsylvania State University, University Park, PA 16802, USA.
Abstract:
Ovarian cancer is the most lethal gynecological malignancy in women. Metformin intake is associated with a reduced incidence of ovarian cancer and increased overall survival rate. We determined the effect of metformin on sphere formation, extracellular matrix invasion, and transcriptome profile of ovarian cancer cells (COVCAR) isolated from ascites of chickens that naturally developed ovarian cancer. We found that metformin treatment significantly decreased sphere formation and invasiveness of COVCAR cells. RNA-Seq data analysis revealed 0, 4, 365 differentially expressed genes in cells treated with 0.5, 1, 2 mM metformin, respectively compared to controls. Transcriptomic and ingenuity pathway analysis (IPA) revealed significant downregulation of MMP7, AICDA, GDPD2, APOC3, APOA1 and predicted inhibition of upstream regulators NFKB, STAT3, TP53 that are involved in epithelial-mesenchymal transition, DNA repair, and lipid metabolism. The analysis revealed significant upregulation of RASD2, IHH, CRABP-1 and predicted activation of upstream regulators VEGF and E2F1 that are associated with angiogenesis and cell cycle. Causal network analysis revealed novel pathways suggesting predicted inhibition of ovarian cancer through master regulator ASCL1 and dataset genes DCX, SEMA6B, HEY2, and KCNIP2. In summary, advanced pathway analysis in IPA revealed novel target genes, upstream regulators, and pathways affected by metformin treatment of COVCAR cells.
Insights
Metformin significantly reduced ovarian cancer cell sphere formation and invasion. This study identified novel gene targets and pathways, including ASCL1, potentially inhibited by metformin.
Area of Science:
- Gynecological Oncology
- Pharmacology
- Genomics
Background:
- Ovarian cancer is a leading cause of cancer death in women.
- Metformin is linked to lower ovarian cancer incidence and improved survival.
Purpose of the Study:
- To investigate metformin's effects on ovarian cancer cell behavior (sphere formation, invasion) and gene expression.
- To analyze the transcriptome profile of chicken ovarian cancer cells (COVCAR) treated with metformin.
Main Methods:
- COVCAR cells were treated with varying metformin concentrations (0.5, 1, 2 mM).
- Sphere formation and extracellular matrix invasion assays were performed.
- RNA-sequencing (RNA-Seq) and Ingenuity Pathway Analysis (IPA) were utilized to analyze gene expression and pathways.
Main Results:
- Metformin significantly decreased COVCAR cell sphere formation and invasiveness.
- Differential gene expression analysis revealed changes in hundreds of genes, with dose-dependent effects.
- IPA identified downregulation of genes (e.g., MMP7, AICDA) and predicted inhibition of regulators (e.g., NFKB, STAT3) involved in key cancer processes.
- Upregulation of genes (e.g., RASD2, IHH) and predicted activation of regulators (e.g., VEGF, E2F1) related to angiogenesis and cell cycle were observed.
- Novel causal networks suggested metformin's potential to inhibit ovarian cancer via master regulator ASCL1.
Conclusions:
- Metformin exhibits anti-cancer properties against ovarian cancer cells by reducing key malignant behaviors.
- Metformin alters the transcriptome of ovarian cancer cells, impacting pathways involved in epithelial-mesenchymal transition, DNA repair, lipid metabolism, angiogenesis, and cell cycle.
- Advanced pathway analysis reveals potential novel therapeutic targets and mechanisms for metformin in ovarian cancer treatment.
