Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1782343660524797952 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4226686 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT zhangning peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT chueaglesh peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT zhangjingwan peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT lixiaoxing peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT liangqiaoyi peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT chenjie peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT chenminhu peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT teohnarci peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT farrellgeoffrey peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT sungjosephjy peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway AT yujun peroxisomeproliferatoractivatedreceptoralphainhibitshepatocarcinogenesisthroughmediatingnfkbsignalingpathway |