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

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 hepatocellular carcinoma (HCC). PPARα-knockout (PPARα(-/-)) mice...

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Autores principales: Zhang, Ning, Chu, Eagle S. H., Zhang, Jingwan, Li, Xiaoxing, Liang, Qiaoyi, Chen, Jie, Chen, Minhu, Teoh, Narci, Farrell, Geoffrey, Sung, Joseph J.Y., Yu, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226686/
https://www.ncbi.nlm.nih.gov/pubmed/25327562
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author Zhang, Ning
Chu, Eagle S. H.
Zhang, Jingwan
Li, Xiaoxing
Liang, Qiaoyi
Chen, Jie
Chen, Minhu
Teoh, Narci
Farrell, Geoffrey
Sung, Joseph J.Y.
Yu, Jun
author_facet Zhang, Ning
Chu, Eagle S. H.
Zhang, Jingwan
Li, Xiaoxing
Liang, Qiaoyi
Chen, Jie
Chen, Minhu
Teoh, Narci
Farrell, Geoffrey
Sung, Joseph J.Y.
Yu, Jun
author_sort Zhang, Ning
collection PubMed
description 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 hepatocellular carcinoma (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(-/-) 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 PPARα(-/-) mice (P < 0.01), with concomitant up-regulation of cyclin-D1 and down-regulation of p15. Moreover, ectopic expression of PPARα in HCC cells significantly suppressed cell proliferation and induced apoptosis. The anti-tumorigenic function of PPARα was mediated via NF-κB as evidenced by inhibition of NF-κB promoter activity, diminution of phosphor-p65, phosphor-p50 and BCL2 levels, and enhancing IkBα protein. Chromatin immunoprecipitation analysis confirmed PPARα directly binds to the IkBα promoter. In conclusion, PPARα deficiency enhances susceptibility to DEN-initiated HCC. PPARα suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting IκBα and NF-κB signaling pathway.
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spelling pubmed-42266862014-11-17 Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway Zhang, Ning Chu, Eagle S. H. Zhang, Jingwan Li, Xiaoxing Liang, Qiaoyi Chen, Jie Chen, Minhu Teoh, Narci Farrell, Geoffrey Sung, Joseph J.Y. Yu, Jun Oncotarget Research Paper 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 hepatocellular carcinoma (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(-/-) 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 PPARα(-/-) mice (P < 0.01), with concomitant up-regulation of cyclin-D1 and down-regulation of p15. Moreover, ectopic expression of PPARα in HCC cells significantly suppressed cell proliferation and induced apoptosis. The anti-tumorigenic function of PPARα was mediated via NF-κB as evidenced by inhibition of NF-κB promoter activity, diminution of phosphor-p65, phosphor-p50 and BCL2 levels, and enhancing IkBα protein. Chromatin immunoprecipitation analysis confirmed PPARα directly binds to the IkBα promoter. In conclusion, PPARα deficiency enhances susceptibility to DEN-initiated HCC. PPARα suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting IκBα and NF-κB signaling pathway. Impact Journals LLC 2014-07-13 /pmc/articles/PMC4226686/ /pubmed/25327562 Text en Copyright: © 2014 Zhang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhang, Ning
Chu, Eagle S. H.
Zhang, Jingwan
Li, Xiaoxing
Liang, Qiaoyi
Chen, Jie
Chen, Minhu
Teoh, Narci
Farrell, Geoffrey
Sung, Joseph J.Y.
Yu, Jun
Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway
title Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway
title_full Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway
title_fullStr Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway
title_full_unstemmed Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway
title_short Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway
title_sort peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating nf-κb signaling pathway
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226686/
https://www.ncbi.nlm.nih.gov/pubmed/25327562
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