Inhibitory Role of Peroxisome Proliferator-Activated Receptor Gamma in Hepatocarcinogenesis in Mice and In Vitro
Inhibitory Role of Peroxisome Proliferator-Activated Receptor Gamma in Hepatocarcinogenesis in Mice and In Vitro
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DOI：
10.1002/hep.23550
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发表时间：
2010-06-01
期刊：
影响因子：
13.5
通讯作者：
Sung, Joseph J. Y.
中科院分区：
文献类型：
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作者：
Yu, Jun;Shen, Bo;Sung, Joseph J. Y.
尽管过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma，PPARgamma）激动剂已被证明能抑制肝细胞癌（hepatocellular carcinoma，HCC）的发展，但PPARgamma在HCC发生中的作用仍不清楚。我们研究了PPAR γ对HCC的治疗效果。在二乙基亚硝胺（DEN）诱导的HCC模型中使用了PPAR γ缺陷型（PPAR γ（+/-））和野生型（PPAR γ（+/+））同窝仔，并用PPAR γ激动剂（罗格列酮）或单独的载体治疗8个月。用表达PPAR γ的腺病毒（Ad-PPAR γ）检测了PPAR γ对肝癌细胞生长和凋亡的影响。与PPARgamma（+/+）小鼠相比，PPARgamma（+/-）小鼠对DEN诱导的HCC更敏感（94%vs62%，P < 0.05），罗格列酮显著降低了PPARgamma（+/+）小鼠的HCC发病率（媒介物62%对治疗24%，P < 0.01），但在PPAR γ（+/-）小鼠中没有，表明PPAR γ抑制肝细胞癌发生。在用Ad-PPAR γ感染的HCC细胞系（Hep 3B）中观察到PPAR γ的显著表达。这种诱导作用明显抑制肝癌细胞的存活率（P < 0.01）。此外，Ad-PPAR γ感染Hep 3B后，S期细胞比例下降（12.92%对11.58%，P < 0.05），G（2）/M期细胞比例下降（38.2%对55.68%，P < 0.001），同时存在关键的G（2）/M期抑制剂cdc 25 C和cdc 2的磷酸化。PPAR γ过表达增加了细胞凋亡（21.47%vs35.02%，P < 0.01），由外源性（Fas和肿瘤坏死因子-α）和内源性（caspase-9、caspase-3、caspase-7和聚[ADP-核糖]聚合酶）途径介导。此外，过氧化物酶体增殖物激活受体γ直接诱导一个假定的肿瘤抑制基因，生长分化因子-15。结论：一个PPAR γ等位基因的缺失足以增加HCC的易感性。PPAR γ通过抑制细胞增殖、诱导G（2）/M期阻滞、凋亡和上调生长分化因子15来抑制肿瘤细胞生长。因此，PPAR γ在肝脏中充当肿瘤抑制基因。（肝脏学2010;51：2008-2019）
Although peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist have been shown to inhibit hepatocellular carcinoma (HCC) development, the role of PPAR gamma in hepatocarcinogenesis remains unclear. We investigated the therapeutic efficacy of PPAR gamma against HCC. PPAR gamma-deficient (PPAR gamma(+/-)) and wild-type (PPAR gamma(+/+)) littermates were used in a diethylnitrosamine (DEN)-induced HCC model and treated with PPAR gamma agonist (rosiglitazone) or the vehicle alone for 8 months. The effects of PPAR gamma on HCC cell growth and apoptosis were examined using PPAR gamma-expressing adenovirus (Ad-PPAR gamma). PPAR gamma(+/-) mice were more susceptible to DEN-induced HCC than PPAR gamma(+/+) mice (94% versus 62%, P < 0.05), and rosiglitazone significantly reduced the incidence of HCC in PPAR gamma(+/+) mice (vehicle 62% versus treatment 24%, P < 0.01), but not in PPAR gamma(+/-) mice, indicating that PPAR gamma suppresses hepatocellular carcinogenesis. A pronounced expression of PPAR gamma was observed in a HCC cell line (Hep3B) infected with Ad-PPAR gamma. Such induction markedly suppressed HCC cell viability (P < 0.01). Further, Hep3B infection with Ad-PPAR gamma 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. PPAR gamma 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, PPAR gamma directly induced a putative tumor suppressor gene, growth differentiation factor-15. Conclusion: Loss of one PPAR gamma allele is sufficient to enhance susceptibility to HCC. PPAR gamma suppresses tumor cell growth through reducing cell proliferation and inducing G(2)/M phase arrest, apoptosis, and up-regulating growth differentiation factor-15. Thus, PPAR gamma acts as a tumor-suppressor gene in the liver. (HEPATOLOGY 2010;51:2008-2019)