| First Author | Zhang N | Year | 2014 |
| Journal | Oncotarget | Volume | 5 |
| Issue | 18 | Pages | 8330-40 |
| PubMed ID | 25327562 | Mgi Jnum | J:312835 |
| Mgi Id | MGI:6791937 | Doi | 10.18632/oncotarget.2212 |
| Citation | Zhang N, et al. (2014) Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-kappaB signaling pathway. Oncotarget 5(18):8330-40 |
| abstractText | Peroxisome proliferator-activated receptor alpha (PPARalpha) ligands have been reported to suppress cancer growth. However, the role of PPARalpha in hepatocarcinogenesis remains unclear. We investigated the functional significance of PPARalpha in HCC. PPARalpha-knockout (PPARalpha-/-) 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 PPARalpha-/- 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 PPARalpha-/- mice (P < 0.01), with concomitant up-regulation of cyclin-D1 and down-regulation of p15. Moreover, ectopic expression of PPARalpha in HCC cells significantly suppressed cell proliferation and induced apoptosis. The anti-tumorigenic function of PPARalpha was mediated via NF-kappaB as evidenced by inhibition of NF-kappaB promoter activity, diminution of phosphor-p65, phosphor-p50 and BCL2 levels, and enhancing IkBalpha protein. Chromatin immunoprecipitation analysis confirmed PPARalphadirectly binds to the IkBalpha promoter. In conclusion, PPARalpha deficiency enhances susceptibility to DEN-initiated HCC. PPARalpha suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting IkappaBalpha and NF-kappaB signaling pathway. |
