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

// Marissa Williams 1, * , Michaela B. Kirschner 1, 2, 13, * , Yuen Yee Cheng 1 , Jacky Hanh 1, 3 , Jocelyn Weiss 4 , Nancy Mugridge 4 , Casey M. Wright 1 , Anthony Linton 1, 2, 5 , Steven C. Kao 1, 2, 6 , J. James B. Edelman 7 , Michael P. Vallely 7, 8 , Brian C. McCaughan 9 , Wendy Cooper 2, 10 , Sonja Klebe 11 , Ruby C.Y. Lin 1, 12 , Himanshu Brahmbhatt 4 , Jennifer MacDiarmid 4 , Nico van Zandwijk 1, 2 , Glen Reid 1, 2 1 Asbestos Diseases Research Institute (ADRI), Sydney, Australia 2 Sydney Medical School, The University of Sydney, Sydney, Australia 3 Faculty of Pharmacy, The University of Sydney, Sydney, Australia 4 EnGeneIC Ltd., Lane Cove, Australia 5 Department of Medical Oncology, Concord Repatriation General Hospital, Sydney, Australia 6 Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia 7 Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital, The Baird Institute and Faculty of Medicine, The University of Sydney, Sydney, Australia 8 Australian School of Advanced Medicine, Macquarie University, Sydney, Australia 9 Sydney Cardiothoracic Surgeons, RPA Medical Centre, Sydney, Australia 10 Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia 11 Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, Australia 12 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia 13 Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland * These authors have contributed equally to this work Correspondence to: Glen Reid, e-mail: glen.reid@sydney.edu.au 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.