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


CONCLUSIONS
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.
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA. Electronic address: chanjohn@obgyn.ucsf.edu.
John K
JK
Chan
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA.
Kevin
K
Blansit
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA.
Tuyen
T
Kiet
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco School of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA 94143, USA.
Alexander
A
Sherman
Department of Medicine, University of California, San Francisco School of Medicine, Veterans Affairs Medical Center, Box 111N2, San Francisco, CA, USA.
Gabriel
G
Wong
Department of Medicine, University of California, San Francisco School of Medicine, Veterans Affairs Medical Center, Box 111N2, San Francisco, CA, USA.
Christine
C
Earle
Department of Medicine, University of California, San Francisco School of Medicine, Veterans Affairs Medical Center, Box 111N2, San Francisco, CA, USA.
Lilly Y W
LY
Bourguignon
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D014162:Transfection
D000970:Antineoplastic Agents; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D002945:Cisplatin
Chemoresistance; Chemosensitivity; MicroRNA; Ovarian cancer; miR-21