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

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 chal...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742203/
https://www.ncbi.nlm.nih.gov/pubmed/26452132
Descripción
Sumario: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.