Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro.
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.


CONCLUSIONS
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.
Yu
Jun
J
Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Hong Kong, China. junyu@cuhk.edu.hk
Shen
Bo
B
Chu
Eagle S H
ES
Teoh
Narci
N
Cheung
Kin-Fai
KF
Wu
Chung-Wah
CW
Wang
Shiyan
S
Lam
Cleo N Y
CN
Feng
Hai
H
Zhao
Junhong
J
Cheng
Alfred S L
AS
To
Ka-Fai
KF
Chan
Henry L Y
HL
Sung
Joseph J Y
JJ
D000256:Adenoviridae; D000477:Alkylating Agents; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004052:Diethylnitrosamine; D020869:Gene Expression Profiling; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D015854:Up-Regulation
D000477:Alkylating Agents; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004052:Diethylnitrosamine