John K Chan1, Kevin Blansit2, Tuyen Kiet2, Alexander Sherman2, Gabriel Wong3, Christine Earle3, Lilly Y W Bourguignon3. 1. 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. 2. 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. 3. Department of Medicine, University of California, San Francisco School of Medicine, Veterans Affairs Medical Center, Box 111N2, San Francisco, CA, USA.
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. Published by Elsevier Inc.
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 cancerpatients 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. Published by Elsevier Inc.
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