Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation.
Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) leads to hepatocellular proliferation and liver carcinomas. The early events mediating these effects are unknown. A novel mechanism by which PPARalpha regulates gene expression and hepatocellular proliferation was uncovered. MicroRNA (miRNA) expression profiling demonstrated that activated PPARalpha 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 PPARalpha 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 PPARalpha-mediated induction of c-myc via let-7C subsequently increased expression of the oncogenic mir-17-92 cluster; these events did not occur in Pparalpha-null mice. Overexpression of let-7C decreased c-myc and mir-17 and suppressed the growth of Hepa-1 cells. Furthermore, using the human PPARalpha-expressing mouse model, which is responsive to Wy-14,643 effects on beta-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 PPARalpha agonist-induced liver proliferation and tumorigenesis.
Shah
Yatrik M
YM
National Cancer Institute, Bethesda, MD 20892, USA.
Morimura
Keiichirou
K
Yang
Qian
Q
Tanabe
Tomotaka
T
Takagi
Mitsuhiro
M
Gonzalez
Frank J
FJ
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008113:Liver Neoplasms / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008957:Models, Genetic; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction
D035683:MicroRNAs; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; C006253:pirinixic acid; D008156:Luciferases