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

Oncotarget. 2015 Nov 3;6(34):36675-88. doi: 10.18632/oncotarget.5383.

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.

Keywords: adrenal cancer; miR-7; nanoparticle therapy; noncoding RNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA, Untranslated / genetics
  • Random Allocation
  • Transfection / methods
  • Xenograft Model Antitumor Assays

Substances

  • MIRN7 microRNA, human
  • MicroRNAs
  • RNA, Untranslated

Associated data

  • GEO/GSE61359