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J Natl Cancer Inst. 2015 May 20;107(7). pii: djv108. doi: 10.1093/jnci/djv108. Print 2015 Jul.

Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers.

Author information

1
: Departments of Pathology (GL, DY, YS, XL, PJ, DC, LH, WZ), Experimental Therapeutics (CRA, GLB), and Gynecologic Oncology and Reproductive Medicine (RR, LSM, AKS), Division of Cancer Medicine (CVP), Center for RNAi and Non-Coding RNA (RR, CVP, LSM, CRA, GLB, AKS, WZ), the University of Texas MD Anderson Cancer Center, Houston, TX; Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China (GL, YW, FX); Department of Pathology (YS) and Epidemiology (KC), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, the Fourth Military Medical University, Xi'an, China (XL); Institute for Systems Biology, Seattle, WA (IS); Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (LDC, DM).
2
: Departments of Pathology (GL, DY, YS, XL, PJ, DC, LH, WZ), Experimental Therapeutics (CRA, GLB), and Gynecologic Oncology and Reproductive Medicine (RR, LSM, AKS), Division of Cancer Medicine (CVP), Center for RNAi and Non-Coding RNA (RR, CVP, LSM, CRA, GLB, AKS, WZ), the University of Texas MD Anderson Cancer Center, Houston, TX; Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China (GL, YW, FX); Department of Pathology (YS) and Epidemiology (KC), Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, the Fourth Military Medical University, Xi'an, China (XL); Institute for Systems Biology, Seattle, WA (IS); Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (LDC, DM). wzhang@mdanderson.org.

Erratum in

Abstract

BACKGROUND:

Chemoresistance is a major challenge in cancer treatment. miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT), which is also associated with chemoresistance. We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers.

METHODS:

We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents. We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity. All statistical tests were two-sided.

RESULTS:

MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P < .0001; TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04). MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51. Systemic delivery of miR-506 in 8-12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36±0.05g vs 0.07±0.02g, P < .001; control miRNA plus olaparib vs miR-506 plus olaparib: 0.32±0.13g vs 0.05±0.02g, P = .045, respectively), thus recapitulating the clinical observation.

CONCLUSIONS:

MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy.

PMID:
25995442
PMCID:
PMC4554255
DOI:
10.1093/jnci/djv108
[Indexed for MEDLINE]
Free PMC Article

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