Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway.
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 fata...
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Public Library of Science (PLoS)
2014-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0097094 |
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| author | Ileabett M Echevarría-Vargas Fatma Valiyeva Pablo E Vivas-Mejía |
| author_facet | Ileabett M Echevarría-Vargas Fatma Valiyeva Pablo E Vivas-Mejía |
| author_sort | Ileabett M Echevarría-Vargas |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4fbaaf8b700d4d748e4eaaa40f685074 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-4fbaaf8b700d4d748e4eaaa40f6850742025-08-20T03:44:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9709410.1371/journal.pone.0097094Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway.Ileabett M Echevarría-VargasFatma ValiyevaPablo E Vivas-MejíaCisplatin 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.https://doi.org/10.1371/journal.pone.0097094 |
| spellingShingle | Ileabett M Echevarría-Vargas Fatma Valiyeva Pablo E Vivas-Mejía Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway. PLoS ONE |
| title | Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway. |
| title_full | Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway. |
| title_fullStr | Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway. |
| title_full_unstemmed | Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway. |
| title_short | Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway. |
| title_sort | upregulation of mir 21 in cisplatin resistant ovarian cancer via jnk 1 c jun pathway |
| url | https://doi.org/10.1371/journal.pone.0097094 |
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