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MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells

Dimitrios Iliopoulos1, Christos Polytarchou, Maria Hatziapostolou

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Science Signaling
|October 15, 2009
PubMed

Insights

The balance between Akt1 and Akt2 influences microRNA levels, controlling cancer cell changes like epithelial-mesenchymal transition (EMT). This Akt-miR-200-E-cadherin axis impacts breast cancer metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The Akt signaling pathway is implicated in human cancer, but the specific roles of its three isoforms (Akt1, Akt2, Akt3) in oncogenesis are not fully understood.
  • MicroRNAs (miRNAs) are key regulators of gene expression and play critical roles in cancer development and progression.

Purpose of the Study:

  • To investigate the distinct contributions of Akt isoforms to oncogenesis.
  • To elucidate the relationship between Akt isoforms, miRNA expression, and the epithelial-mesenchymal transition (EMT) in cancer.

Main Methods:

  • Expression of individual Akt isoforms in a triple Akt knockout cell line.
  • MicroRNA profiling of growth factor-stimulated cells.
  • Knockdown experiments of Akt1 and Akt2 in TGFbeta-treated MCF10A cells.
  • Analysis of primary and metastatic human breast cancers.

Main Results:

  • Each Akt isoform exhibited unique miRNA signatures.
  • Akt2 expression decreased miR-200 family abundance.
  • Akt1 knockdown promoted TGFbeta-induced EMT and stem cell-like phenotypes.
  • Down-regulation of miR-200 correlated with increased invasiveness in mouse models.
  • A correlation was observed between the Akt1/Akt2 ratio, miR-200 levels, E-cadherin expression, and breast cancer metastasis in human samples.

Conclusions:

  • The induction of EMT is regulated by microRNAs whose abundance is dependent on the balance between Akt1 and Akt2.
  • The Akt-miR-200-E-cadherin axis is a potential mechanism controlling breast cancer metastasis.

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