microRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma

// Anthony R. Glover 1, 2, 9, * , Jing Ting Zhao 1, 2, * , Anthony J. Gill 2, 3 , Jocelyn Weiss 4 , Nancy Mugridge 4 , Edward Kim 1, 2 , Alex L. Feeney 1, 2 , Julian C. Ip 1, 2 , Glen Reid 5 , Stephen Clarke 2, 6 , Patsy S.H. Soon 7 , Bruce G. Robinson 1, 2, 8 , Himanshu Brahmbhatt 4 , Jennifer A. MacDiarmid 4 , Stan B. Sidhu 1, 2, 9 1 Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia 2 Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia 3 Department of Anatomical Pathology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia 4 EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia 5 Asbestos Diseases Research Institute, University of Sydney, Concord, Sydney, NSW, Australia 6 Department of Oncology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia 7 Ingham Institute for Applied Medical Research, University of New South Wales, Liverpool, NSW, Australia 8 Department of Endocrinology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia 9 University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, St Leonards, Sydney, NSW, Australia * These authors have contributed equally to this work Correspondence to: Stan B. Sidhu, e-mail: stanley.sidhu@sydney.edu.au Keywords: noncoding RNA, miR-7, nanoparticle therapy, adrenal cancer Received: July 12, 2015      Accepted: September 18, 2015      Published: October 01, 2015 ABSTRACT Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor response to conventional treatment. Replacing tumor suppressor microRNAs (miRNAs) offer a novel therapy, however systemic delivery remains challenging. A number of miRNAs have been described to be under-expressed in ACC however it is not known if they form a part of ACC pathogenesis. Here we report that microRNA-7–5p (miR-7) reduces cell proliferation in vitro and induces G 1 cell cycle arrest. Systemic miR-7 administration in a targeted, clinically safe delivery vesicle ( EGFR EDV TM nanocells) reduces ACC xenograft growth originating from both ACC cell lines and primary ACC cells. Mechanistically, miR-7 targets Raf-1 proto-oncogene serine/threonine kinase (RAF1) and mechanistic target of rapamycin (MTOR). Additionally, miR-7 therapy in vivo leads to inhibition of cyclin dependent kinase 1 (CDK1). In patient ACC samples, CDK1 is overexpressed and miR-7 expression inversely related. In summary, miR-7 inhibits multiple oncogenic pathways and reduces ACC growth when systemically delivered using EDV TM nanoparticles. This data is the first study in ACC investigating the possibility of miRNAs replacement as a novel therapy.