Oncotarget

Research Papers:

miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression

Michael R. Epis, Keith M. Giles, Dianne J. Beveridge, Kirsty L. Richardson, Patrick A. Candy, Lisa M. Stuart, Jacqueline Bentel, Ronald J. Cohen and Peter J. Leedman _

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Oncotarget. 2017; 8:55116-55134. https://doi.org/10.18632/oncotarget.18664

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Abstract

Michael R. Epis1,*, Keith M. Giles1,4,*, Dianne J. Beveridge1,*, Kirsty L. Richardson1, Patrick A. Candy1, Lisa M. Stuart1, Jacqueline Bentel2, Ronald J. Cohen5 and Peter J. Leedman1,3

1Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, 6009, Australia

2Department of Anatomical Pathology, Fiona Stanley Hospital, Murdoch, WA, 6150, Australia

3School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA, 6008, Australia

4Department of Dermatology, New York University Langone Medical Center, New York, NY, 10016, USA

5Uropath Pty Ltd, West Leederville, WA, 6007, Australia

*These authors have contributed equally to this work

Correspondence to:

Peter J. Leedman, email: [email protected]

Keywords: miR-331-3p, prostate cancer, Aurora Kinase inhibitor, co-treatment

Received: March 26, 2017     Accepted: May 22, 2017     Published: June 27, 2017

ABSTRACT

RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tumors was significantly decreased compared to non-malignant matched tissue. Analysis of publicly available PCa gene expression data sets showed miR-331-3p expression negatively correlated with Gleason Score, tumor stage, lymph node involvement and PSA value, and was significantly down regulated in tumor tissue relative to normal prostate tissue. Overexpression of miR-331-3p reduced PCa cell growth, migration and colony formation, as well as xenograft tumor initiation, proliferation and survival of mice. Microarray analysis identified seven novel targets of miR-331-3p in PCa. The 3’-untranslated regions of PLCγ1 and RALA were confirmed as targets of miR-331-3p, with mutation analyses confirming RALA as a direct target. Expression of miR-331-3p or RALA siRNA in PCa cells reduced RALA expression, proliferation, migration and colony formation in vitro. RALA expression positively correlated with Gleason grade in two separate studies, as well as in a PCa tissue microarray. Co-treatment using siRALA with an Aurora Kinase inhibitor (AKi-II) decreased colony formation of PCa cells while the combination of AKi-II with miR-331-3p resulted in significant reduction of PCa cell proliferation in vitro and PCa xenograft growth in vivo. Thus, miR-331-3p directly targets the RALA pathway and the addition of the AKi-II has a synergistic effect on tumor growth inhibition, suggesting a potential role as combination therapy in PCa.


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