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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor worldwide and is the second leading cause of cancer-related deaths in China [1, 2]
Having noted that PPARα-/mice were remarkably sensitive to DEN-induced hepatocarcinogenesis, we examined the relationship of PPARα to the key regulators of cell proliferation and apoptosis in livers from these mice and investigated its tumor suppressive role as well as molecular bases by which PPARα exerts this function in vitro
Activation of the PPARα by its agonists has been shown to inhibit cancer growth including HCC cell lines [7, 19], there have been no studies to mechanistically define the role of PPARα in hepatocarcinogenesis
Summary
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor worldwide and is the second leading cause of cancer-related deaths in China [1, 2]. The antiinflammatory and anti-angiogenic effects of PPARα promote the suppression of tumor growth by improving microenvironment. In light of these findings, we propose that PPARα may act as a potential tumor suppressor against hepatocarcinogenesis. Elucidating the role of PPARα whether acting as a tumor promoter or suppressor is important in understanding its contribution to liver carcinogenesis and may provide clues in developing effective treatments against this malignance. Having noted that PPARα-/mice were remarkably sensitive to DEN-induced hepatocarcinogenesis, we examined the relationship of PPARα to the key regulators of cell proliferation and apoptosis in livers from these mice and investigated its tumor suppressive role as well as molecular bases by which PPARα exerts this function in vitro. Our findings illustrate that PPARα is a potential tumor suppressor in HCC and raise the tantalizing possibility that PPARα has therapeutic potential in treating this lethal cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
