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Molecular and Cellular Biology, June 2007, p. 4238-4247, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00317-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Peroxisome Proliferator-Activated Receptor {alpha} Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation{triangledown} ,{dagger}

Yatrik M. Shah, Keiichirou Morimura, Qian Yang, Tomotaka Tanabe, Mitsuhiro Takagi, and Frank J. Gonzalez*

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Received 21 February 2007/ Returned for modification 29 March 2007/ Accepted 5 April 2007

Activation of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) leads to hepatocellular proliferation and liver carcinomas. The early events mediating these effects are unknown. A novel mechanism by which PPAR{alpha} regulates gene expression and hepatocellular proliferation was uncovered. MicroRNA (miRNA) expression profiling demonstrated that activated PPAR{alpha} was a major regulator of hepatic miRNA expression. Of particular interest, let-7C, an miRNA important in cell growth, was inhibited following 4-h treatment and 2-week and 11-month sustained treatment with the potent PPAR{alpha} agonist Wy-14,643 in wild-type mice. let-7C was shown to target c-myc via direct interaction with the 3' untranslated region of c-myc. The PPAR{alpha}-mediated induction of c-myc via let-7C subsequently increased expression of the oncogenic mir-17-92 cluster; these events did not occur in Ppar{alpha}-null mice. Overexpression of let-7C decreased c-myc and mir-17 and suppressed the growth of Hepa-1 cells. Furthermore, using the human PPAR{alpha}-expressing mouse model, which is responsive to Wy-14,643 effects on ß-oxidation and serum triglycerides but resistant to hepatocellular proliferation and tumorigenesis, we demonstrated a critical role for let-7C in liver oncogenesis. Wy-14,643 treatment did not inhibit let-7C or induce c-myc and mir-17 expression. These observations reveal a let-7C signaling cascade critical for PPAR{alpha} agonist-induced liver proliferation and tumorigenesis.

* Corresponding author. Mailing address: Building 37, Room 3106, National Cancer Institute, Bethesda, MD 20892. Phone: (301) 496-9067. Fax: (301) 496-8419. E-mail: fjgonz{at}helix.nih.gov

{triangledown} Published ahead of print on 16 April 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2007, p. 4238-4247, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00317-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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