MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream-regulated gene family members in adrenocortical cancer

Int J Cancer. 2018 Aug 15;143(4):944-957. doi: 10.1002/ijc.31363. Epub 2018 Mar 30.


Adrenocortical carcinoma (ACC) is a tumor with poor prognosis in which overexpression of a panel of microRNAs has been associated with malignancy but a very limited number of investigations on their role in ACC pathogenesis have been conducted. We examined the involvement of miR-483-5p and miR-139-5p in adrenocortical cancer aggressiveness. Using bioinformatics predictions and mRNA/miRNA expression profiles, we performed an integrated analysis to identify inversely correlated miRNA-mRNA pairs in ACC. We identified N-myc downstream-regulated gene family members 2 and 4 (NDRG2 and NDRG4) as targets of miR-483-5p and miR-139-5p, respectively. NDRG2 and NDRG4 expressions were inversely correlated respectively with miR-483-5p and miR-139-5p levels in aggressive ACC samples from two independent cohorts of 20 and 44 ACC. Moreover, upregulation of miR-139-5p and downregulation of NDRG4 demonstrated a striking prognostic value. A direct interaction between miR-483-5p or miR-139-5p and their targets was demonstrated in reporter assays. Downregulation of miR-483-5p or miR-139-5p in the ACC cell lines NCI-H295R and SW13 increased NDRG2 or NDRG4 mRNA and protein expression, compromised adrenocortical cancer cell invasiveness and anchorage-independent growth. MiR-483-5p or miR-139-5p overexpression and NDRG2 or NDRG4 inhibition produce similar changes, which are rescued by NDRG2 or NDRG4 ectopic expression. We established that key factors mediating epithelial-to-mesenchymal transition are downstream effectors of miR-483-5p/NDRG2 and miR-139-5p/NDRG4 pathways. Collectively, our data show for the first time that miR-483-5p/NDRG2 and miR-139-5p/NDRG4 axes promote ACC aggressiveness, with potential implications for prognosis and therapeutic interventions in adrenocortical malignancies.

Keywords: N-myc downstream-regulated gene family; NDRG2; NDRG4; adrenocortical cancer; invasion; miR-139-5p; miR-483-5p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Cortex Neoplasms / pathology*
  • Apoptosis / physiology
  • Cell Adhesion / physiology
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Down-Regulation
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic*
  • Genes, myc*
  • HEK293 Cells
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Multigene Family*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Neoplasm Staging
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Prognosis
  • RNA, Messenger / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation


  • 3' Untranslated Regions
  • MIRN139 microRNA, human
  • MIRN483 microRNA, human
  • MicroRNAs
  • Muscle Proteins
  • NDRG2 protein, human
  • NDRG4 protein, human
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Tumor Suppressor Proteins