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

// Ning Zhang 1,2 , Eagle S. H. Chu 1,3 , Jingwan Zhang 1,3 , Xiaoxing Li 1,3 , Qiaoyi Liang 1,3 , Jie Chen 2 , Minhu Chen 2 , Narci Teoh 4 , Geoffrey Farrell 4 , Joseph J.Y. Sung 1,3 and Jun Yu 1 1 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China 2 Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China 3 Gastrointestinal Cancer Biology & Therapeutics Laboratory, CUHK-Shenzhen Research Institute, Shenzhen, China 4 Australian National University Medical School at The Canberra Hospital, Canberra, Australia Correspondence: Jun Yu, email: // Keywords : PPARα, tumor suppressor, nuclear factor-kappa B, signaling pathway, hepatocellular carcinoma Received : June 16, 2014 Accepted : July 11, 2014 Published : July 13, 2014 Abstract 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 -/- 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 PPARαdirectly 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.