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Abstract
Peroxisome proliferator chemicals are classic non-genotoxic carcinogens. These agents
cause liver cancers when chronically administered to rats and mice. Peroxisome proliferators
include the widely prescribed lipid and cholesterol lowering fibrate drugs. In contrast
to the results in rodents, there is no evidence that fibrates are associated with
elevated risk of liver cancer or any other neoplasms in humans thus indicating a species
difference in the hepatocarcinogenic response. The biological effects of peroxisome
proliferators are mediated by the peroxisome proliferator-activated receptor (PPAR)alpha.
Pparalpha-null mice are resistant to all of the pleiotropic effects of peroxisome
proliferators, including cell proliferation and hepatocarcinogenesis. The mechanism
of hepatocellular proliferation involves downregulation of the microRNA let-7c gene
by PPARalpha. Let-7c controls levels of proliferative c-myc by destabilizing its mRNA.
Thus, upon suppression of let-7c, c-myc mRNA and protein are elevated resulting in
enhanced hepatocellular proliferation. In contrast, PPARalpha-humanized mice, that
respond to Wy-14,643 by lower serum triglycerides and induction of genes encoding
fatty acid metabolizing enzymes, are resistant to peroxisome proliferator-induced
cell proliferation and cancer. These mice do not exhibit downregulation of let-7c
gene expression thus forming the basis for the resistance to hepatocellular carcinogenesis.