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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Curcumin modulates cell type-specific miRNA networks to induce cytotoxicity in ovarian cancer cells
Febina Ravindran1, Anisha Mhatre1, Jinsha Koroth1
1Institute of Bioinformatics and Applied Biotechnology, Electronic city phase 1, Bangalore, India.
Aim:
To understand the epigenetic role of curcumin, a natural polyphenolic compound extracted from the spice Curcuma longa in inducing cytotoxicity in two molecularly distinct ovarian cancer cell lines: PA1 and A2780.
Materials And Methods:
An integrated mRNA-miRNA sequence analysis was performed to determine the curcumin-induced mRNA-miRNA regulatory networks in the induction of cytotoxicity. The miRNA-mRNA pathways, the miRNAs and their targets implicated in apoptosis, autophagy, DNA damage, and stemness markers were validated. Gene/miRNA expressions were validated using qPCR and protein expressions by western blotting. Curcumin-induced oncogenic /tumor-suppressor miRNAs were profiled utilising the oncomiRdb database. Similarly, the expressions of oncogenes/tumor suppressor genes were profiled and correlated with the TCGA ovarian cancer dataset. A dual luciferase assay was performed to investigate the interaction of miR-199a-5p to its direct target, DDR1.
Key Findings:
The expression of several miRNAs demonstrated an inverse correlation with their respective direct targets. In curcumin-treated PA1 cells, miR-335-5p target ATG5 (autophagic), and OCT4 (pluripotent gene) were downregulated, miR-32a target PTEN (tumor suppressor) was upregulated, miR-1285 target P53 (tumor suppressor) was upregulated, and both miR-182-5p and miR-503-3p target BCL2, were down-regulated. Contrastingly, in curcumin-treated A2780 cells, miR-181a-3p target ATG5, miR-30a-5p, and miR-216a target BECN1 (autophagic) were upregulated, and miR-129a-5p target BCL2 were downregulated. The reversal of the oncomiR/TSmiR profile revealed suppression of oncogenic processes by curcumin. Curcumin treatment induced a moderate cisplatin-sensitisation effect and impaired epithelial-to-mesenchymal transition (EMT) characteristics. Curcumin also regulated the miR-199a-5p/DDR1 axis with a decrease in collagen deposition.
Significance:
The activity of curcumin is cell-type specific. Distinct miRNA regulatory networks were activated to induce multiple modes of cellular cytotoxicity in these ovarian cancer cells. This study further highlights the molecular mechanism of curcumin action in ovarian cancers establishing its candidacy as a promising drug candidate.
Insights
Curcumin
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Research
Background:
- Curcumin, a natural compound from Curcuma longa, possesses potential anti-cancer properties.
- Ovarian cancer exhibits complex molecular heterogeneity, necessitating targeted therapeutic strategies.
- Epigenetic modifications play a crucial role in ovarian cancer development and progression.
Purpose of the Study:
- To elucidate the epigenetic mechanisms by which curcumin induces cytotoxicity in distinct ovarian cancer cell lines (PA1 and A2780).
- To identify curcumin-modulated microRNA (miRNA)-mRNA regulatory networks involved in ovarian cancer cell death pathways.
Main Methods:
- Integrated mRNA-miRNA sequencing to map regulatory networks.
- Quantitative PCR (qPCR) and Western blotting for gene and protein expression validation.
- Bioinformatic analysis using oncomiRdb and TCGA datasets.
- Dual luciferase assay to confirm specific miRNA-target interactions.
Main Results:
- Curcumin induced cell-type specific miRNA expression changes, inversely correlating with target genes involved in apoptosis, autophagy, and stemness.
- Specific miRNAs (e.g., miR-335-5p, miR-32a, miR-1285) and their targets (e.g., ATG5, OCT4, PTEN, P53) were modulated differently in PA1 and A2780 cells.
- Curcumin demonstrated cisplatin-sensitizing effects, impaired epithelial-to-mesenchymal transition (EMT), and regulated the miR-199a-5p/DDR1 axis, reducing collagen deposition.
Conclusions:
- Curcumin's cytotoxic effects in ovarian cancer are mediated by distinct, cell-specific miRNA regulatory networks.
- These findings highlight curcumin's potential as a therapeutic agent by targeting multiple cellular pathways.
- The study establishes a molecular basis for curcumin's efficacy in ovarian cancer treatment.
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