Oncotarget

Research Papers:

miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma

Marissa Williams, Michaela B. Kirschner, Yuen Yee Cheng, Jacky Hanh, Jocelyn Weiss, Nancy Mugridge, Casey M. Wright, Anthony Linton, Steven C. Kao, J James B. Edelman, Michael P. Vallely, Brian C. McCaughan, Wendy Cooper, Sonja Klebe, Ruby C.Y. Lin, Himanshu Brahmbhatt, Jennifer MacDiarmid, Nico van Zandwijk and Glen Reid _

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Oncotarget. 2015; 6:23480-23495. https://doi.org/10.18632/oncotarget.4346

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Abstract

Marissa Williams1,*, Michaela B. Kirschner1,2,13,*, Yuen Yee Cheng1, Jacky Hanh1,3, Jocelyn Weiss4, Nancy Mugridge4, Casey M. Wright1, Anthony Linton1,2,5, Steven C. Kao1,2,6, J. James B. Edelman7, Michael P. Vallely7,8, Brian C. McCaughan9, Wendy Cooper2,10, Sonja Klebe11, Ruby C.Y. Lin1,12, Himanshu Brahmbhatt4, Jennifer MacDiarmid4, Nico van Zandwijk1,2, Glen Reid1,2

1Asbestos Diseases Research Institute (ADRI), Sydney, Australia

2Sydney Medical School, The University of Sydney, Sydney, Australia

3Faculty of Pharmacy, The University of Sydney, Sydney, Australia

4EnGeneIC Ltd., Lane Cove, Australia

5Department of Medical Oncology, Concord Repatriation General Hospital, Sydney, Australia

6Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia

7Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital, The Baird Institute and Faculty of Medicine, The University of Sydney, Sydney, Australia

8Australian School of Advanced Medicine, Macquarie University, Sydney, Australia

9Sydney Cardiothoracic Surgeons, RPA Medical Centre, Sydney, Australia

10Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia

11Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, Australia

12School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia

13Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland

*These authors have contributed equally to this work

Correspondence to:

Glen Reid, e-mail: [email protected]

Keywords: tumor suppressor, mesothelioma, microRNA, miR-193a

Received: January 19, 2015     Accepted: June 12, 2015     Published: June 22, 2015

ABSTRACT

Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention.


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