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MicroRNA Expression Profiles in Human Samples and Cell Lines Revealed Nine miRNAs Associated with Cisplatin
Marienid Flores-Colón1,2, Mariela Rivera-Serrano2,3, Víctor G Reyes-Burgos1,2
1Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA.
Abstract:
Metastasis and drug resistance are major contributors to cancer-related fatalities worldwide. In ovarian cancer (OC), a staggering 70% develop resistance to the front-line therapy, cisplatin. Despite proposed mechanisms, the molecular events driving cisplatin resistance remain unclear. Dysregulated microRNAs (miRNAs) play a role in OC initiation, progression, and chemoresistance, yet few studies have compared miRNA expression in OC samples and cell lines. This study aimed to identify key miRNAs involved in the cisplatin resistance of high-grade-serous-ovarian-cancer (HGSOC), the most common gynecological malignancy. MiRNA expression profiles were conducted on RNA isolated from formalin-fixed-paraffin-embedded human ovarian tumor samples and HGSOC cell lines. Nine miRNAs were identified in both sample types. Targeting these with oligonucleotide miRNA inhibitors (OMIs) reduced proliferation by more than 50% for miR-203a, miR-96-5p, miR-10a-5p, miR-141-3p, miR-200c-3p, miR-182-5p, miR-183-5p, and miR-1206. OMIs significantly reduced migration for miR-183-5p, miR-203a, miR-296-5p, and miR-1206. Molecular pathway analysis revealed that the nine miRNAs regulate pathways associated with proliferation, invasion, and chemoresistance through PTEN, ZEB1, FOXO1, and SNAI2. High expression of miR-1206, miR-10a-5p, miR-141-3p, and miR-96-5p correlated with poor prognosis in OC patients according to the KM plotter database. These nine miRNAs could be used as targets for therapy and as markers of cisplatin response.
Insights
This study identified nine microRNAs (miRNAs) crucial for ovarian cancer cisplatin resistance. Inhibiting these miRNAs significantly reduced cancer cell proliferation and migration, offering potential new therapeutic targets for ovarian cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastasis and drug resistance are primary causes of cancer mortality.
- Ovarian cancer (OC) frequently develops resistance to cisplatin, the standard therapy, with 70% of patients affected.
- The molecular mechanisms underlying cisplatin resistance in OC are not fully understood, despite the known role of microRNAs (miRNAs) in cancer progression.
Purpose of the Study:
- To identify key microRNAs (miRNAs) involved in cisplatin resistance in high-grade serous ovarian cancer (HGSOC).
- To evaluate the therapeutic potential of targeting identified miRNAs in HGSOC.
- To establish miRNAs as potential biomarkers for predicting cisplatin response in ovarian cancer.
Main Methods:
- MiRNA expression profiling was performed on RNA from human ovarian tumor samples and HGSOC cell lines.
- Oligonucleotide miRNA inhibitors (OMIs) were used to target identified miRNAs.
- Cell proliferation and migration assays were conducted to assess the functional impact of miRNA inhibition.
- Bioinformatic analysis was used to identify regulated pathways and patient prognosis correlation.
Main Results:
- Nine miRNAs were consistently identified in both tumor samples and cell lines.
- Targeting specific miRNAs with OMIs reduced HGSOC cell proliferation by over 50% and migration.
- Pathway analysis indicated these miRNAs regulate proliferation, invasion, and chemoresistance via PTEN, ZEB1, FOXO1, and SNAI2.
- High expression of four specific miRNAs (miR-1206, miR-10a-5p, miR-141-3p, miR-96-5p) correlated with poor prognosis in OC patients.
Conclusions:
- The identified nine miRNAs are implicated in HGSOC cisplatin resistance.
- Targeting these miRNAs with inhibitors shows therapeutic promise for overcoming chemoresistance.
- These miRNAs can serve as potential biomarkers for predicting cisplatin response and patient outcomes in ovarian cancer.
