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Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for

Yatrik M Shah1, Keiichirou Morimura, Qian Yang

  • 1National Cancer Institute, Bethesda, MD 20892, USA.

Molecular and Cellular Biology
|April 18, 2007
PubMed

Insights

Peroxisome proliferator-activated receptor alpha (PPARalpha) activation drives liver cancer by inhibiting let-7C microRNA, which normally suppresses cell growth. This pathway is crucial for PPARalpha agonist-induced liver proliferation and tumorigenesis.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Oncology

Background:

  • Peroxisome proliferator-activated receptor alpha (PPARalpha) activation is linked to liver cancer development.
  • The precise early molecular events driving PPARalpha-mediated hepatocellular proliferation remain largely unknown.

Purpose of the Study:

  • To elucidate a novel mechanism by which PPARalpha regulates gene expression and hepatocellular proliferation.
  • To investigate the role of microRNAs (miRNAs) in PPARalpha-mediated liver oncogenesis.

Main Methods:

  • MicroRNA (miRNA) expression profiling in wild-type and Pparalpha-null mice treated with PPARalpha agonist Wy-14,643.
  • Analysis of let-7C targeting of c-myc and its downstream effects on the mir-17-92 cluster.
  • Validation in a human PPARalpha-expressing mouse model resistant to hepatocellular proliferation.

Main Results:

  • PPARalpha activation significantly altered hepatic miRNA expression, notably inhibiting let-7C.
  • let-7C directly targets c-myc, and its inhibition by PPARalpha leads to c-myc and mir-17-92 cluster upregulation.
  • In a humanized mouse model resistant to proliferation, Wy-14,643 did not inhibit let-7C or induce c-myc/mir-17, confirming let-7C's critical role.

Conclusions:

  • A let-7C signaling cascade is essential for PPARalpha agonist-induced liver proliferation and tumorigenesis.
  • PPARalpha agonists inhibit let-7C, leading to c-myc induction and subsequent oncogenic events.
  • Targeting the let-7C pathway may offer therapeutic strategies for PPARalpha-related liver diseases.

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