title: MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma.
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 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.
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.|Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.|University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Glover
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.|Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Jing Ting
authors.initials: JT
authors.lastname: Zhao
authors.affiliation: Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.|Department of Anatomical Pathology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Weiss
authors.affiliation: EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mugridge
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.|Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.|Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Alex L
authors.initials: AL
authors.lastname: Feeney
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.|Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Ip
authors.affiliation: Asbestos Diseases Research Institute, University of Sydney, Concord, Sydney, NSW, Australia.
authors.forename: Glen
authors.initials: G
authors.lastname: Reid
authors.affiliation: Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.|Department of Oncology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Clarke
authors.affiliation: Ingham Institute for Applied Medical Research, University of New South Wales, Liverpool, NSW, Australia.
authors.forename: Patsy S H
authors.initials: PS
authors.lastname: Soon
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.|Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.|Department of Endocrinology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
authors.affiliation: EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Brahmbhatt
authors.affiliation: EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: MacDiarmid
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.|Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia.|University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, St Leonards, Sydney, NSW, Australia.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Sidhu
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000628:therapy*; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics*; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D022661:RNA, Untranslated / Q000235:genetics; D011897:Random Allocation; D014162:Transfection / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D022661:RNA, Untranslated; C000715470:MAS1 protein, human; C549242:MIRN7-1 microRNA, human
keywords: adrenal cancer; miR-7; nanoparticle therapy; noncoding RNA