miR-125b acts as a tumor suppressor in breast tumorigenesis via its novel direct targets ENPEP, CK2-α, CCNJ, and MEGF9

PLoS One. 2013 Oct 3;8(10):e76247. doi: 10.1371/journal.pone.0076247. eCollection 2013.

Abstract

MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. To explore the dysregulation of miRNAs in breast cancer, a genome-wide expression profiling of 939 miRNAs was performed in 50 breast cancer patients. A total of 35 miRNAs were aberrantly expressed between breast cancer tissue and adjacent normal breast tissue and several novel miRNAs were identified as potential oncogenes or tumor suppressor miRNAs in breast tumorigenesis. miR-125b exhibited the largest decrease in expression. Enforced miR-125b expression in mammary cells decreased cell proliferation by inducing G2/M cell cycle arrest and reduced anchorage-independent cell growth of cells of mammary origin. miR-125b was found to perform its tumor suppressor function via the direct targeting of the 3'-UTRs of ENPEP, CK2-α, CCNJ, and MEGF9 mRNAs. Silencing these miR-125b targets mimicked the biological effects of miR-125b overexpression, confirming that they are modulated by miR-125b. Analysis of ENPEP, CK2-α, CCNJ, and MEGF9 protein expression in breast cancer patients revealed that they were overexpressed in 56%, 40-56%, 20%, and 32% of the tumors, respectively. The expression of ENPEP and CK2-α was inversely correlated with miR-125b expression in breast tumors, indicating the relevance of these potential oncogenic proteins in breast cancer patients. Our results support a prognostic role for CK2-α, whose expression may help clinicians predict breast tumor aggressiveness. In particular, our results show that restoration of miR-125b expression or knockdown of ENPEP, CK2-α, CCNJ, or MEGF9 may provide novel approaches for the treatment of breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Casein Kinase II / genetics*
  • Casein Kinase II / metabolism
  • Cell Line
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cluster Analysis
  • Cyclins / genetics*
  • Cyclins / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Genes, Tumor Suppressor*
  • Glutamyl Aminopeptidase / genetics*
  • Glutamyl Aminopeptidase / metabolism
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • RNA Interference

Substances

  • 3' Untranslated Regions
  • Cyclins
  • MEGF9 protein, human
  • MIRN125 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Nerve Tissue Proteins
  • cyclin J, human
  • Casein Kinase II
  • ENPEP protein, human
  • Glutamyl Aminopeptidase

Grant support

This work was supported by the “Banco Bilbao Vizcaya Argentaria” (BBVA) Foundation Grant number 056/09. MLL is an FIS investigator (CP03/00101). A. Feliciano is funded by a FIS fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.