Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Hong Kong, China.
Hepatology. 2010 Jun;51(6):2008-19. doi: 10.1002/hep.23550.
Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonist have been shown to inhibit hepatocellular carcinoma (HCC) development, the role of PPARgamma in hepatocarcinogenesis remains unclear. We investigated the therapeutic efficacy of PPARgamma against HCC. PPARgamma-deficient (PPARgamma(+/-)) and wild-type (PPARgamma(+/+)) littermates were used in a diethylnitrosamine (DEN)-induced HCC model and treated with PPARgamma agonist (rosiglitazone) or the vehicle alone for 8 months. The effects of PPARgamma on HCC cell growth and apoptosis were examined using PPARgamma-expressing adenovirus (Ad-PPARgamma). PPARgamma(+/-) mice were more susceptible to DEN-induced HCC than PPARgamma(+/+) mice (94% versus 62%, P < 0.05), and rosiglitazone significantly reduced the incidence of HCC in PPARgamma(+/+) mice (vehicle 62% versus treatment 24%, P < 0.01), but not in PPARgamma(+/-) mice, indicating that PPARgamma suppresses hepatocellular carcinogenesis. A pronounced expression of PPARgamma was observed in a HCC cell line (Hep3B) infected with Ad-PPARgamma. Such induction markedly suppressed HCC cell viability (P < 0.01). Further, Hep3B infection with Ad-PPARgamma revealed a decreased proportion of cells in S-phase (12.92% versus 11.58%, P < 0.05), with arrest at G(2)/M phase (38.2% versus 55.68%, P < 0.001), and there was concomitant phosphorylation of the key G(2)/M phase inhibitors cdc25C and cdc2. PPARgamma overexpression increased cell apoptosis (21.47% versus 35.02%, P < 0.01), mediated by both extrinsic (Fas and tumor necrosis factor-alpha) and intrinsic (caspase-9, caspase-3, caspase-7, and poly[ADP-ribose] polymerase) pathways. Moreover, PPARgamma directly induced a putative tumor suppressor gene, growth differentiation factor-15.
Loss of one PPARgamma allele is sufficient to enhance susceptibility to HCC. PPARgamma suppresses tumor cell growth through reducing cell proliferation and inducing G(2)/M phase arrest, apoptosis, and up-regulating growth differentiation factor-15. Thus, PPARgamma acts as a tumor-suppressor gene in the liver.
尽管过氧化物酶体增殖物激活受体 γ（PPARγ）激动剂已被证明可抑制肝细胞癌（HCC）的发展，但 PPARγ 在肝癌发生中的作用仍不清楚。我们研究了 PPARγ 对 HCC 的治疗功效。使用二乙基亚硝胺（DEN）诱导的 HCC 模型中的 PPARγ 缺陷（PPARγ(+/-)）和野生型（PPARγ(+/+)）同窝仔鼠，并单独用 PPARγ 激动剂（罗格列酮）或载体处理 8 个月。使用表达 PPARγ 的腺病毒（Ad-PPARγ）检查 PPARγ 对 HCC 细胞生长和凋亡的影响。PPARγ(+/-)小鼠比 PPARγ(+/+)小鼠更容易受到 DEN 诱导的 HCC（94%比 62%，P<0.05），罗格列酮显著降低了 PPARγ(+/+)小鼠的 HCC 发生率（载体 62%比治疗 24%，P<0.01），但对 PPARγ(+/-)小鼠没有影响，表明 PPARγ 抑制肝细胞癌发生。在感染 Ad-PPARγ 的 HCC 细胞系（Hep3B）中观察到 PPARγ 的明显表达。这种诱导显著抑制 HCC 细胞活力（P<0.01）。此外，Hep3B 感染 Ad-PPARγ 导致 S 期细胞比例降低（12.92%比 11.58%，P<0.05），G2/M 期阻滞（38.2%比 55.68%，P<0.001），并且关键的 G2/M 期抑制剂 cdc25C 和 cdc2 同时磷酸化。PPARγ 过表达增加细胞凋亡（21.47%比 35.02%，P<0.01），通过外源性（Fas 和肿瘤坏死因子-α）和内源性（caspase-9、caspase-3、caspase-7 和多聚[ADP-核糖]聚合酶）途径介导。此外，PPARγ 直接诱导了一种假定的肿瘤抑制基因，生长分化因子-15。
一个 PPARγ 等位基因的缺失足以增强 HCC 的易感性。PPARγ 通过减少细胞增殖和诱导 G2/M 期阻滞、凋亡以及上调生长分化因子-15 来抑制肿瘤细胞生长。因此，PPARγ 在肝脏中作为肿瘤抑制基因发挥作用。
