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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

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

Zhang Ning N Chu Eagle S H ES Zhang Jingwan J Li Xiaoxing X Liang Qiaoyi Q Chen Jie J Chen Minhu M Teoh Narci N Farrell Geoffrey G Sung Joseph J Y JJ Yu Jun J

Oncotarget 20140901 18

Peroxisome proliferator-activated receptor alpha (PPARα) ligands have been reported to suppress cancer growth. However, the role of PPARα in hepatocarcinogenesis remains unclear. We investigated the functional significance of PPARα in HCC. PPARα-knockout (PPARα-/-) 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 PPARα-/- m ...[more]

PMID: 25327562

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Project description:UnlabelledCystic fibrosis-associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up-regulation of toll-like receptor 4/nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB)-dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis-associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator-activated receptor-γ (PPAR-γ), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild-type and from Cftr-knockout mice exposed to lipopolysaccharide. We found that in CFTR-defective biliary epithelium expression of PPAR-γ is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) up-regulates PPAR-γ-dependent genes, while inhibiting the activation of NF-κB and the secretion of proinflammatory cytokines (lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, granulocyte colony-stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR-γ agonists modulate NF-κB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-κB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate-induced portal endotoxemia.ConclusionThese studies unravel a novel function of PPAR-γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes.

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

Publications

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

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