title: miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition.
abstract: BACKGROUND
  Expression of BRCA1 is commonly decreased in sporadic ovarian cancer, and this is associated with platinum sensitivity and favorable prognosis. However, multiple mechanisms underlying low BRCA1 expression are not fully understood.
  
  
  METHODS
  A bioinformatics-driven microRNA (miR) library screening was used to identify miRs that regulate BRCA1 expression. The effects of miR-9 on cisplatin (cDDP) and PARP inhibitor sensitivity were measured in ovarian cancer cells and C13* xenograft mice (n = 6 per group). The roles of miR-9 on prognosis were assessed in a cohort of ovarian cancer patients (n = 113) with Kaplan-Meier and Cox proportional hazards analyses. All statistical tests were two-sided.
  
  
  RESULTS
  Reverse miR library screening revealed that miR-9 reduced the normalized luciferase activity to 60.3% (95% confidence interval [CI] = 52.0% to 68.5%; P < .001). miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells. Treatment with miR-9 agomiR sensitized BRCA1-proficient C13* xenograft tumors to cisplatin and AG014699. In serous ovarian cancer, higher levels of miR-9 were inversely correlated with BRCA1 expression (Spearman rank correlation: R (2) = 0.379; P = .003). Patients with higher levels of miR-9 had better chemotherapy response, platinum sensitivity, and longer progression-free survival (PFS) (high vs low miR-9 expression: median PFS = 26.4 months, 95% CI = 13.8 to 39.0 months vs median PFS = 15.4 months, 95% CI = 6.8 to 23.9 months, P = .01).
  
  
  CONCLUSIONS
  miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer. miR-9 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage and may impact ovarian cancer therapy.
authors.affiliation: Affiliation of authors: Cancer Biology Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (CS, NL, ZY, BZ, YH, DW, YF, PW, PC, DM, JZ, GC); Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China (XY).
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Sun
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Zongyuan
authors.initials: Z
authors.lastname: Yang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.forename: Danhui
authors.initials: D
authors.lastname: Weng
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Pingbo
authors.initials: P
authors.lastname: Chen
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Yang
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000187:drug effects / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology*; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D007211:Indoles; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib; D002945:Cisplatin