microRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma
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Anthony R. Glover1,2,9,*, Jing Ting Zhao1,2,*, Anthony J. Gill2,3, Jocelyn Weiss4, Nancy Mugridge4, Edward Kim1,2, Alex L. Feeney1,2, Julian C. Ip1,2, Glen Reid5, Stephen Clarke2,6, Patsy S.H. Soon7, Bruce G. Robinson1,2,8, Himanshu Brahmbhatt4, Jennifer A. MacDiarmid4, Stan B. Sidhu1,2,9
1Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia
2Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia
3Department of Anatomical Pathology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
4EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia
5Asbestos Diseases Research Institute, University of Sydney, Concord, Sydney, NSW, Australia
6Department of Oncology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
7Ingham Institute for Applied Medical Research, University of New South Wales, Liverpool, NSW, Australia
8Department of Endocrinology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
9University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, St Leonards, Sydney, NSW, Australia
*These authors have contributed equally to this work
Stan B. Sidhu, e-mail: [email protected]
Keywords: noncoding RNA, miR-7, nanoparticle therapy, adrenal cancer
Received: July 12, 2015 Accepted: September 18, 2015 Published: October 01, 2015
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 G1 cell cycle arrest. Systemic miR-7 administration in a targeted, clinically safe delivery vesicle (EGFREDVTM 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 EDVTM nanoparticles. This data is the first study in ACC investigating the possibility of miRNAs replacement as a novel therapy.
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