title: miR-509-3p is clinically significant and strongly attenuates cellular migration and multi-cellular spheroids in ovarian cancer.
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.
authors.affiliation: Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Robertson
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lykke
authors.initials: L
authors.lastname: Pedersen
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Emilia
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.
authors.forename: Anadulce
authors.initials: A
authors.lastname: Hernandez-Herrera
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Rowat
authors.affiliation: Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.
authors.forename: Sagar L
authors.initials: SL
authors.lastname: Patil
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
authors.forename: Clara K
authors.initials: CK
authors.lastname: Chan
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Upal
authors.initials: U
authors.lastname: Basu-Roy
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Mansukhani
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Andy
authors.initials: A
authors.lastname: Chu
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Payal
authors.initials: P
authors.lastname: Sipahimalani
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Reanne
authors.initials: R
authors.lastname: Bowlby
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Brooks
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Yussanne
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Moore
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Jacquie E
authors.initials: JE
authors.lastname: Schein
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Thoracic Medical Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.|Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000032:analysis; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D010750:Phosphoproteins / Q000096:biosynthesis; D018874:Spheroids, Cellular / Q000473:pathology; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C571982:MIRN509 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: YAP1; extracellular matrix (ECM); microRNA 509-3p; ovarian cancer; spheroid formation