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miR-509-3p is clinically significant and strongly attenuates cellular migration and multi-cellular spheroids in ovarian cancer.

  • Author(s): Pan, Yinghong
  • Robertson, Gordon
  • Pedersen, Lykke
  • Lim, Emilia
  • Hernandez-Herrera, Anadulce
  • Rowat, Amy C
  • Patil, Sagar L
  • Chan, Clara K
  • Wen, Yunfei
  • Zhang, Xinna
  • Basu-Roy, Upal
  • Mansukhani, Alka
  • Chu, Andy
  • Sipahimalani, Payal
  • Bowlby, Reanne
  • Brooks, Denise
  • Thiessen, Nina
  • Coarfa, Cristian
  • Ma, Yussanne
  • Moore, Richard A
  • Schein, Jacquie E
  • Mungall, Andrew J
  • Liu, Jinsong
  • Pecot, Chad V
  • Sood, Anil K
  • Jones, Steven JM
  • Marra, Marco A
  • Gunaratne, Preethi H
  • et al.
Abstract

Ovarian cancer presents as an aggressive, advanced stage cancer with widespread metastases that depend primarily on multicellular spheroids in the peritoneal fluid. To identify new druggable pathways related to metastatic progression and spheroid formation, we integrated microRNA and mRNA sequencing data from 293 tumors from The Cancer Genome Atlas (TCGA) ovarian cancer cohort. We identified miR-509-3p as a clinically significant microRNA that is more abundant in patients with favorable survival in both the TCGA cohort (P = 2.3E-3), and, by in situ hybridization (ISH), in an independent cohort of 157 tumors (P < 1.0E-3). We found that miR-509-3p attenuated migration and disrupted multi-cellular spheroids in HEYA8, OVCAR8, SKOV3, OVCAR3, OVCAR4 and OVCAR5 cell lines. Consistent with disrupted spheroid formation, in TCGA data miR-509-3p's most strongly anti-correlated predicted targets were enriched in components of the extracellular matrix (ECM). We validated the Hippo pathway effector YAP1 as a direct miR-509-3p target. We showed that siRNA to YAP1 replicated 90% of miR-509-3p-mediated migration attenuation in OVCAR8, which contained high levels of YAP1 protein, but not in the other cell lines, in which levels of this protein were moderate to low. Our data suggest that the miR-509-3p/YAP1 axis may be a new druggable target in cancers with high YAP1, and we propose that therapeutically targeting the miR-509-3p/YAP1/ECM axis may disrupt early steps in multi-cellular spheroid formation, and so inhibit metastasis in epithelial ovarian cancer and potentially in other cancers.

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