Abstract
BackgroundOvarian cancer is the leading cause of death from gynecologic cancer in women worldwide. According to the National Cancer Institute, ovarian cancer has the highest mortality rate among all the reproductive cancers in women. Advanced stage diagnosis and chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The most commonly employed chemotherapeutic drug for ovarian cancer treatment is cis-platin. As with most chemotherapeutic drugs, many patients eventually become resistant to cis-platin and therefore, diminishing its effect. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies.MethodsThe present study is focused on identifying the differential expression of regulatory microRNAs (miRNAs) between cis-platin sensitive (A2780), and cis-platin resistant (A2780/CP70) cell lines. Cell proliferation assays were conducted to test the sensitivity of the two cell lines to cis-platin. Differential expression patterns of miRNA between cis-platin sensitive and cis-platin resistant cell lines were analyzed using novel LNA technology.ResultsOur results revealed changes in expression of 11 miRNAs out of 1,500 miRNAs analyzed. Out of the 11 miRNAs identified, 5 were up-regulated in the A2780/CP70 cell line and 6 were down regulated as compared to cis-platin sensitive A2780 cells. Our microRNA data was further validated by quantitative real-time PCR for these selected miRNAs. Ingenuity Pathway Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed for the selected miRNAs and their putative targets to identify the potential pathways and networks involved in cis-platin resistance.ConclusionsOur data clearly showed the differential expression of 11 miRNAs in cis-platin resistant cells, which could potentially target many important pathways including MAPK, TGF-β signaling, actin cytoskeleton, ubiquitin mediated proteasomal pathway, Wnt signaling, mTOR signaling, Notch signaling, apoptosis, and many other signaling pathways. Manipulation of one or more of these miRNAs could be an important approach for ovarian cancer chemotherapy.
Highlights
Ovarian cancer is the leading cause of death from gynecologic cancer in women worldwide
This leads to one question: what mechanisms cause cells to become resistant to cisplatin? Cis-platin reacts with DNA to induce distinctive biological changes that results in damaged DNA and starts the irrevocable apoptosis process [9]
Cell viability assay To investigate the difference in the sensitivity of A2780 and A2780/CP70 cells for cis-platin, cell viability assays were performed
Summary
Ovarian cancer is the leading cause of death from gynecologic cancer in women worldwide. Cis-platin is an inorganic platinum-based compound formally named cisdiamminedichloroplatinum (II) (CDDP) Initially, this drug is successful in 80-90% of the patients, eventually cells become resistant [6,7]. Resistance to cisplatin occurs in nearly one third of all women during treatment and is prevalent in most patients treated for a recurrent disease [8]. This leads to one question: what mechanisms cause cells to become resistant to cisplatin? When cisplatin penetrates cells its chloride channels are replaced by water molecules, forming aquated species that can react with intracellular macromolecules, creating cis-platin adducts. Since 2006, much speculation has arisen on the correlation between miRNA, gene expression, and even carcinogenesis [12]
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