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

• Published in: Oncotarget Vol. 6; no. 34; pp. 36675 - 36688
• Main Authors: Glover, Anthony R, Zhao, Jing Ting, Gill, Anthony J, Weiss, Jocelyn, Mugridge, Nancy, Kim, Edward, Feeney, Alex L, Ip, Julian C, Reid, Glen, Clarke, Stephen, Soon, Patsy S H, Robinson, Bruce G, Brahmbhatt, Himanshu, MacDiarmid, Jennifer A, Sidhu, Stan B
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 03.11.2015
• Subjects: Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - therapy; Adrenocortical Carcinoma - genetics; Adrenocortical Carcinoma - therapy; Animals; Cell Line, Tumor; Cell Proliferation; Female; Genetic Therapy - methods; Humans; Immunohistochemistry; Mice; Mice, Nude; MicroRNAs - administration & dosage; MicroRNAs - genetics; Prognosis; Random Allocation; Research Paper; RNA, Untranslated - genetics; Transfection - methods; Xenograft Model Antitumor Assays; miR-7; noncoding RNA; adrenal cancer; nanoparticle therapy
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5383

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.