期刊
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
卷 107, 期 7, 页码 -出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djv108
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资金
- National Institutes of Health [U24CA143835, P50 CA083639, P50 CA098258, U54 CA151668, CA016672]
- CPRIT [RP110595]
- Ovarian Cancer Research Fund, Inc.
- Blanton-Davis Ovarian Cancer Research Program
- Asian Fund for Cancer Research
- AIRC grant from Associazione Italiana per la Ricerca sul Cancro [IG10302]
- National Science Foundation of China [81101673, 81472761, 81201651]
- Tianjin Science and Technology Committee Foundation [14JCYBJC25300, 09ZCZDSF04700, 15RCGFSY00108]
- Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) in China
- National Key Scientific and Technological Project [2011ZX0 9307-001-04]
- National Foundation for Cancer Research
- Diane Denson Tobola Fellowship in Ovarian Cancer Research
- Harold C. and Mary L. Daily Endowment Fund
- Elsa Pardee Foundation in University of Pittsburgh
- National Cancer Institute [CA009666]
- DOM Advanced Scholar Program
- A. Lavoy Moore Endowment Fund
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.
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