Academic Journal
MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC
| العنوان: | MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC |
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| المؤلفون: | Sun, Chenggong, Cao, Wenyu, Qiu, Chunping, Li, Chengcheng, Dongol, Samina, Zhang, Zhiwei, Dong, Ruifen, Song, Kun, Yang, Xingsheng, Zhang, Qing, Kong, Beihua |
| المساهمون: | National Natural Science Foundation of China, Natural Science Foundation of Shandong Province, China Postdoctoral Science Foundation |
| المصدر: | Journal of Hematology & Oncology ; volume 13, issue 1 ; ISSN 1756-8722 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2020 |
| الوصف: | Background PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. Methods We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. Results High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P < 0.05, Qilu P < 0.05; OS: TCGA P < 0.05, Qilu P < 0.01). MiR-509-3 could impair the proliferation, migration, and invasion ability but enhance the sensitivity to Olaparib of ovarian cancer cell in vitro and in vivo by directly targeting HMGA2 and RAD51. In two PDX cases (PDX1 and PDX9), miR-509-3 could significantly increase the sensitivity to Olaparib along with the decrease of RAD51 positive rate (mean tumor weight NC + Olaparib vs. miR-509 + Olaparib; PDX1 P < 0.05, PDX9 P < 0.05). Additionally, in PDX8, miR-509-3 treatment dramatically reversed the Olaparib insensitivity ( P < 0.05) by downregulating RAD51 expression. RAD51 functional detection revealed that all Olaparib sensitive cases exhibited low RAD51 positive rate (lesser than 50%) in treated groups. Furthermore, among the four HR gene mutation patients, three harbored HR core gene mutation and were sensitive to Olaparib while the remaining one with ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1186/s13045-020-0844-0 |
| DOI: | 10.1186/s13045-020-0844-0.pdf |
| DOI: | 10.1186/s13045-020-0844-0/fulltext.html |
| الاتاحة: | http://dx.doi.org/10.1186/s13045-020-0844-0 http://link.springer.com/content/pdf/10.1186/s13045-020-0844-0.pdf http://link.springer.com/article/10.1186/s13045-020-0844-0/fulltext.html |
| Rights: | http://creativecommons.org/licenses/by/4.0/ ; http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.E9D8EDDF |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s13045-020-0844-0 |
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