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