The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer

Abstract Background MicroRNAs have been implicated in tumorigenesis, drug resistance, and prognosis in cancer. We investigated the role of microRNA-21 ( miR-21 ) in regulating ovarian cancer drug resistance. Methods We used parental and cisplatin resistant ovarian cell lines to demonstrate the role...

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Bibliographic Details
Published in:Gynecologic oncology 2014-03, Vol.132 (3), p.739-744
Main Authors: Chan, John K, Blansit, Kevin, Kiet, Tuyen, Sherman, Alexander, Wong, Gabriel, Earle, Christine, Bourguignon, Lilly Y.W
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Apoptosis - genetics
Cell Line, Tumor
Chemoresistance
Chemosensitivity
Cisplatin - pharmacology
Drug Resistance, Neoplasm
Female
Hematology, Oncology and Palliative Medicine
Humans
MicroRNA
MicroRNAs - antagonists & inhibitors
MicroRNAs - biosynthesis
MicroRNAs - genetics
miR-21
Obstetrics and Gynecology
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Ovarian Neoplasms - pathology
Transfection
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Summary:Abstract Background MicroRNAs have been implicated in tumorigenesis, drug resistance, and prognosis in cancer. We investigated the role of microRNA-21 ( miR-21 ) in regulating ovarian cancer drug resistance. Methods We used parental and cisplatin resistant ovarian cell lines to demonstrate the role of miR-21 in drug resistance and investigated the gene targets of miR-21 . Fresh tumor specimens were used to validate our in vitro findings. Results Cisplatin resistant ovarian cells were four-fold more resistant compared to the parental cell line. MiR-21 was overexpressed in the resistant cell line on microRNA microarray, which was subsequently validated with qRT-PCR. Using anti-microRNA inhibitors, we demonstrated that miR-21 attenuation reversed the drug resistant phenotype in both the resistant and parental cell lines. The inhibition of miR-21 induced apoptosis based on annexin V-FITC immunostaining. Using Western blot analysis, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, and attenuated apoptosis inhibitor c-IAP2. Using 101 specimens from advanced ovarian cancer patients enrolled in The Cancer Genome Atlas, we found that women with tumors that overexpressed miR-21 were associated with a shorter progression-free survival. Conclusion Our data suggest that miR-21 regulates drug resistance via apoptosis and cellular survival pathways. Targeting miR-21 may have clinical utility in the treatment of resistant ovarian cancer.
ISSN:0090-8258
1095-6859
DOI:10.1016/j.ygyno.2014.01.034