Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-?B signaling pathway.

ABSTRACT: Peroxisome proliferator-activated receptor alpha (PPAR?) ligands have been reported to suppress cancer growth. However, the role of PPAR? in hepatocarcinogenesis remains unclear. We investigated the functional significance of PPAR? in HCC. PPAR?-knockout (PPAR?-/-) mice were more susceptible to diethylnitrosamine (DEN)-induced HCC at 6 months compared with wild-type (WT) littermates (80% versus 43%, P < 0.05). In resected HCCs, TUNEL-positive apoptotic cells were significantly less in PPAR?-/- mice than in WT mice (P < 0.01), commensurate with a reduction in cleaved caspase-3 and caspase-7 protein expression. Ki-67 staining showed increased cell proliferation in PPAR?-/- mice (P < 0.01), with concomitant up-regulation of cyclin-D1 and down-regulation of p15. Moreover, ectopic expression of PPAR? in HCC cells significantly suppressed cell proliferation and induced apoptosis. The anti-tumorigenic function of PPAR? was mediated via NF-?B as evidenced by inhibition of NF-?B promoter activity, diminution of phosphor-p65, phosphor-p50 and BCL2 levels, and enhancing IkB? protein. Chromatin immunoprecipitation analysis confirmed PPAR?directly binds to the IkB? promoter. In conclusion, PPAR? deficiency enhances susceptibility to DEN-initiated HCC. PPAR? suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting I?B? and NF-?B signaling pathway.

SUBMITTER: Zhang N 

PROVIDER: S-EPMC4226686 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature