Lu Jie, Imamura Kazuhiro, Nomura Sachiyo, Mafune Ken-ichi, Nakajima Atsushi, Kadowaki Takashi, Kubota Naoto, Terauchi Yasuo, Ishii Genichiro, Ochiai Atsushi, Esumi Hiroyasu, Kaminishi Michio
Department of Gastrointestinal Surgery, Faculty of Medicine, University of Tokyo, Japan.
Cancer Res. 2005 Jun 1;65(11):4769-74. doi: 10.1158/0008-5472.CAN-04-2293.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is known to be expressed in several cancers, and the treatment of these cancer cells with PPARgamma ligands often induces cell differentiation and apoptosis. Recently, the chemopreventive potential of PPARgamma ligands on colon carcinogenesis was reported, although the effect of PPARgamma on colon carcinogenesis and the mechanism of the effect remain controversial. In this study, we attempted to elucidate the role of PPARgamma in gastric carcinogenesis and explored the possible use of PPARgamma ligand as a chemopreventive agent for gastric cancer. N-methyl-N-nitrosourea (MNU, 240 ppm) was given in drinking water for 10 weeks to induce gastric cancer in PPARgamma wild-type (+/+) and heterozygous-deficient (+/-) mice, followed by treatment with PPARgamma ligand [troglitazone, 0.15% (w/w) in powder food] or the vehicle alone for 42 weeks. At the end of the experiment, PPARgamma (+/-) mice were more susceptible to MNU-induced gastric cancer than wild-type (+/+) mice (89.5%/55.5%), and troglitazone significantly reduced the incidence of gastric cancer in PPARgamma (+/+) mice (treatment 55.5%/vehicle 9%) but not in PPARgamma (+/-) mice. The present study showed that (a) PPARgamma suppresses gastric carcinogenesis, (b) the PPARgamma ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and (c) troglitazone's chemopreventive effect is dependent on PPARgamma.
已知过氧化物酶体增殖物激活受体γ（PPARγ）在多种癌症中表达，用PPARγ配体处理这些癌细胞通常会诱导细胞分化和凋亡。最近，有报道称PPARγ配体对结肠癌发生具有化学预防潜力，尽管PPARγ对结肠癌发生的影响及其作用机制仍存在争议。在本研究中，我们试图阐明PPARγ在胃癌发生中的作用，并探索将PPARγ配体用作胃癌化学预防剂的可能性。给PPARγ野生型（+/+）和杂合缺陷型（+/-）小鼠饮用含N-甲基-N-亚硝基脲（MNU，240 ppm）的水10周以诱导胃癌，随后用PPARγ配体[曲格列酮，粉末状食物中含0.15%（w/w）]或单独使用载体处理42周。实验结束时，PPARγ（+/-）小鼠比野生型（+/+）小鼠更易患MNU诱导的胃癌（89.5%/55.5%），曲格列酮显著降低了PPARγ（+/+）小鼠的胃癌发生率（处理组55.5%/载体组9%），但对PPARγ（+/-）小鼠无效。本研究表明：（a）PPARγ抑制胃癌发生；（b）PPARγ配体曲格列酮是一种潜在的胃癌化学预防剂；（c）曲格列酮的化学预防作用依赖于PPARγ。
