Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2017; 8(10):17406.

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

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

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Oncotarget. 2016; 7:25930-25948. https://doi.org/10.18632/oncotarget.8412

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Abstract

Yinghong Pan1,*, Gordon Robertson2,*, Lykke Pedersen3, Emilia Lim2, Anadulce Hernandez-Herrera1, Amy C. Rowat4, Sagar L. Patil1, Clara K. Chan4, Yunfei Wen5, Xinna Zhang5,6, Upal Basu-Roy9, Alka Mansukhani9, Andy Chu2, Payal Sipahimalani2, Reanne Bowlby2, Denise Brooks2, Nina Thiessen2, Cristian Coarfa14, Yussanne Ma2, Richard A. Moore2, Jacquie E. Schein2, Andrew J. Mungall2, Jinsong Liu8, Chad V. Pecot10, Anil K. Sood5,6,7,8, Steven J.M. Jones2,12,13, Marco A. Marra2,13, Preethi H. Gunaratne1,11

1Department of Biochemistry and Biology, University of Houston, Houston, TX, USA

2Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada

3Department of Biology, University of Copenhagen, Copenhagen, Denmark

4Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA

5Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

6Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

7Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

8Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

9Department of Microbiology, New York University School of Medicine, New York, NY, USA

10UNC Lineberger Comprehensive Cancer Center, Thoracic Medical Oncology, University of North Carolina, Chapel Hill, NC, USA

11Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

12Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada

13Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

14Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

*These authors contributed equally to this work

Correspondence to:

Preethi H. Gunaratne, email: [email protected]

Keywords: microRNA 509-3p, ovarian cancer, extracellular matrix (ECM), YAP1, spheroid formation

Received: August 26, 2015     Accepted: March 13, 2016     Published: March 27, 2016

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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