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Upregulation of miR-21 in Cisplatin Resistant Ovarian Cancer via JNK-1/c-Jun Pathway
Open accessAbstract
Cisplatin has been the most accepted drug for the treatment of ovarian cancer for almost 40 years. Although the majority of patients with ovarian cancer respond to front-line platinum combination chemotherapy, many patients will develop cisplatin-resistance disease, which is extremely rapid and fatal. Although various mechanisms of cisplatin resistance have been postulated, the key molecules involved in such resistance have not been identified. MiRNAs are endogenously expressed small non-coding RNAs, which are evolutionarily conserved and function as post-transcriptional regulators of gene expression. Dysregulation of miRNAs have been associated with cancer initiation, progression and drug resistance. The oncogenic miRNA-21, one of the best-studied miRNAs, is upregulated in almost all human cancers. However, the regulation of miR-21 in cisplatin resistant ovarian cancer cells has not been assessed. In this study, we measured the miR-21 expression by real-time PCR and found upregulation of miR-21 in cisplatin resistant compared with cisplatin sensitive ovarian cancer cells. Chromatin immunoprecipitation studies demonstrated the association of the c-Jun transcription factor to the pri-mir-21 DNA promoter regions. Blocking the JNK-1, the major activator of c-Jun phosphorylation, reduced the expression of pre-mir-21 and increased the expression of its well-known target gene, PDCD4. Overexpression of miR-21 in cisplatin sensitive cells decreased PDCD4 levels and increased cell proliferation. Finally, targeting miR-21 reduced cell growth, proliferation and invasion of cisplatin resistant ovarian cancer cells. These results suggest that the JNK-1/c-Jun/miR-21 pathway contributes to the cisplatin resistance of ovarian cancer cells and demonstrated that miR-21 is a plausible target to overcome cisplatin resistance.
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“miRNAs play a key role in the progression of malignant tumors, they are considered potential anti-tumor therapeutic targets24, 25.”
From miR-21-5p Inhibits the Proliferation, Migration, and Invasion of Glioma by Targeting S100A10 (2023) · cites this paper as [24]
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Metadata
- Authors
- Echevarría-Vargas, I. M., Valiyeva, F., & Vivas-Mejía, P. E.
- Affiliations
- University of Puerto Rico, Medical Sciences Campus (PR)
- University of Puerto Rico System (PR)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-05-27
- Volume
- 9
- Issue
- 5
- Pages
- e97094
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4035252
- OpenAlex
- W2077670883
- Cited by
- 118
- References
- 53
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 13 · 2022: 14 · 2021: 13 · 2020: 12 · 2019: 10 · 2018: 8 · 2017: 8 · 2016: 8 · 2015: 16 · 2014: 2
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-12-26)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Cancer Institute (K22CA166226)
- National Institute of General Medical Sciences (R25GM061838)
- National Institute on Minority Health and Health Disparities (U54MD008149)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- miR-21, cisplatin resistance, ovarian cancer, JNK1, c-Jun, JNK/c-Jun signaling pathway, PDCD4, microRNA regulation, cell proliferation, cell invasion, drug resistance
- MeSH terms
- Antineoplastic Agents, Cell Movement, Cisplatin, Female, Humans, Ovarian Neoplasms, Promoter Regions, Genetic, RNA, Messenger, Tumor Cells, Cultured, Blotting, Western, RNA-Binding Proteins, Apoptosis, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, Chromatin Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 8, Cell Proliferation, Apoptosis Regulatory Proteins, Real-Time Polymerase Chain Reaction
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