| Autor: |
Guoyan Liu, Da Yang, Rajesha Rupaimoole, Pecot, Chad V., Yan Sun, Mangala, Lingegowda S., Xia Li, Ping Ji, Cogdell, David, Limei Hu, Yingmei Wang, Rodriguez-Aguayo, Cristian, Lopez-Berestein, Gabriel, Shmulevich, Ilya, De Cecco, Loris, Kexin Chen, Mezzanzanica, Delia, Fengxia Xue, Sood, Anil K., Wei Zhang |
| Předmět: |
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| Zdroj: |
JNCI: Journal of the National Cancer Institute; 7/15/2015, Vol. 107 Issue 7, p1-12, 12p, 7 Graphs |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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