Ota Kyoko, Ito Kiyoshi, Suzuki Takashi, Saito Sumika, Tamura Mitsutoshi, Hayashi Shin-ichi, Okamura Kunihiro, Sasano Hironobu, Yaegashi Nobuo
Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4200-8. doi: 10.1158/1078-0432.CCR-05-1833.
In this study, we evaluated the correlation between endometrial carcinoma and peroxisome proliferator-activated receptor gamma (PPARgamma) expression and assessed whether PPARgamma ligands influence carcinoma growth.
We examined the presence and cellular distribution of PPARgamma protein in 42 normal endometria, 32 endometria with hyperplasia, and 103 endometria with endometrial carcinoma by immunohistochemistry. We then compared PPARgamma mRNA expression in endometrial carcinoma with that in normal endometria using real-time reverse transcription-PCR. We subsequently confirmed expression of PPARgamma mRNA by real-time reverse transcription-PCR and PPARgamma protein by immunoblotting in endometrial carcinoma cell lines (Ishikawa, Sawano, and RL95-2 cells). We further examined the effects of PPARgamma agonist 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a naturally occurring PPARgamma ligand, to these endometrial carcinoma cell lines. We also examined the status of apoptosis and p21 mRNA expression of these endometrial carcinoma cell lines following addition of 15d-PGJ2.
PPARgamma immunoreactivity was detected in 11 of 23 (48%) of proliferative-phase endometrium, 14 of 19 (74%) of secretory-phase endometrium, 27 of 32 (84%) of endometrial hyperplasia, and 67 of 103 (65%) of carcinoma cases. PPARgamma immunoreactivity was significantly lower in endometrial carcinoma than in secretory-phase endometrium (P = 0.012) and endometrial hyperplasia (P = 0.006). There was a significant positive association between the status of PPARgamma and p21 expression in endometrial carcinoma (P < 0.0001). There was a significant negative association between the body mass index and PPARgamma labeling index of carcinoma tissue in the patients with endometrial carcinoma (P < 0.0001). PPARgamma mRNA was expressed abundantly in normal endometria but not in endometrial carcinoma. We showed that PPARgamma agonist 15d-PGJ2 inhibited cell proliferation and induced p21 mRNA of endometrial carcinoma cell lines.
We showed the expression of PPARgamma in human endometrial carcinoma and the effects of PPARgamma ligand in endometrial carcinoma cells. These findings suggest that a PPARgamma ligand, 15d-PGJ2, has antiproliferative activity against endometrial carcinoma.
在本研究中，我们评估了子宫内膜癌与过氧化物酶体增殖物激活受体γ（PPARγ）表达之间的相关性，并评估PPARγ配体是否影响癌生长。
我们通过免疫组织化学检查了42例正常子宫内膜、32例子宫内膜增生和103例子宫内膜癌中PPARγ蛋白的存在和细胞分布。然后，我们使用实时逆转录PCR比较了子宫内膜癌与正常子宫内膜中PPARγ mRNA的表达。随后，我们通过实时逆转录PCR和免疫印迹法在子宫内膜癌细胞系（Ishikawa、Sawano和RL95-2细胞）中证实了PPARγ mRNA的表达和PPARγ蛋白的表达。我们进一步研究了PPARγ激动剂15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2），一种天然存在的PPARγ配体，对这些子宫内膜癌细胞系的影响。我们还研究了添加15d-PGJ2后这些子宫内膜癌细胞系的凋亡状态和p21 mRNA表达情况。
在23例增殖期子宫内膜中的11例（48%）、19例分泌期子宫内膜中的14例（74%）、32例子宫内膜增生中的27例（84%）和103例癌病例中的67例（65%）中检测到PPARγ免疫反应性。子宫内膜癌中的PPARγ免疫反应性显著低于分泌期子宫内膜（P = 0.012）和子宫内膜增生（P = 0.006）。在子宫内膜癌中，PPARγ状态与p21表达之间存在显著正相关（P < 0.0001）。在子宫内膜癌患者中，癌组织的体重指数与PPARγ标记指数之间存在显著负相关（P < 0.0001）。PPARγ mRNA在正常子宫内膜中大量表达，但在子宫内膜癌中不表达。我们表明，PPARγ激动剂15d-PGJ2抑制子宫内膜癌细胞系的细胞增殖并诱导p21 mRNA。
我们展示了PPARγ在人子宫内膜癌中的表达以及PPARγ配体在子宫内膜癌细胞中的作用。这些发现表明，PPARγ配体15d-PGJ2对子宫内膜癌具有抗增殖活性。
