过氧化物酶增殖物活化受体γ在胰腺癌生长中的调节作用

Regulatory effects of peroxisome proliferator-activated receptor γ on the growth of pancreatic carcinoma

目的 探讨过氧化物酶增殖物活化受体γ(PPARγ)在人胰腺癌生长中的调节作用。方法 应用逆转录 (RT) PCR检测胰腺癌细胞系SW 1990中PPARγ和维甲酸受体α(RXRα)的表达。培养细胞经PPARγ配体 15 脱氧 前列腺素J2 (15d PGJ2 )及RXRα配体 9 顺式 维甲酸 (9 cis RA)作用后 ,用四唑氮蓝还原法测定细胞活力 ,并评价药物的抗增殖效果。建立裸鼠胰腺癌移植瘤模型 ,并予以PPARγ激动剂罗格列酮体内干预 ,75d后处死裸鼠 ,测量移植瘤的大小 ,计算抑瘤率。应用免疫组化观察移植瘤组织中增殖细胞核抗原 (PCNA)的表达。结果 RT PCR结果显示SW1990细胞系存在PPARγ和RXRαmRNA表达。 15d PGJ2 和 9 cis RA及其联合应用对胰腺癌细胞的增殖具有抑制作用 ,且作用呈剂量依赖性。 9 cis RA对 15d PGJ2 抑制胰腺癌细胞增殖具有协同效应。罗格列酮治疗组裸鼠移植瘤的平均体积和重量均显著低于对照组 ,抑瘤率达 80 7%。免疫组化显示治疗组和对照组移植瘤组织中均表达PCNA ,但治疗组的阳性表达强度和表达区域均呈下降趋势。结论 PPARγ的活化在体内外均对胰腺癌的生长呈负向调节作用 ,提示PPARγ可能是胰腺癌治疗的一个新分子靶点。RXRα的激活可协同增强PPARγ激动剂的抗增殖作用。

Objective To examine the effects of peroxisome proliferator-activated receptor (PPAR)γ activation on the growth of human pancreatic carcinoma both in vitro and in vivo. Methods The expression of PPARγ and RXRα were examined by RT-PCR. SW1990 pancreatic cancer cells were treated with 9-cis-RA, ligand of PPARγ,15d-PGJ_2, and both. Antiproliferative effect was evaluated with cell viability by using MTT assay. Pancreatic cancer xenograft tumor model was established in nude mice by inoculating SW1990 cells subcutaneously and rosiglitazone, a PPARγ activator, was administered via water drinking in experimental group. The nude mice were sacrificed after 75 days, the volume and weight of the xenograft tumor were measured. Expression of PCNA was observed by immunohistochemical staining. Results RT-PCR showed that PPARγ and RXRα mRNA were expressed in SW1990 cell line. MTT assay demonstrated that 15d-PGJ_2, 9-cis-RA and the combination of both had a potent inhibitory effect on the growth of SW1990 cells with a dose-dependent manner. SW1990 cells were suppressed to more than 50% of the control at the concentration of 10 μmol/L 15d-PGJ_2,20μmol/L 9-cis-RA and 5 μmol/L 15d-PGJ_2 plus 10 μmol/L 9-cis-RA, respectively. 9-cis-RA had a synergic action with 15d- PGJ_2 on the growth inhibition of pancreatic carcinoma. In vivo studies, rosiglitazone suppressed the growth of pancreatic carcinoma in a statistically significant manner ( P <0.05). The average tumor volume and tumor weight in the experimental group were less than those in the control group, the growth inhibition rate of rosiglitazone was 80.7%. PCNA was present in both groups, but immunohistochemistry showed a down-regulation trend of PCNA in the experimental group as compared with the control group. Conclusions Activation of PPARγ exerts a negative regulatory effect on the growth of pancreatic carcinoma both in vitro and in vivo. These results suggest that PPARγ might be a novel therapeutic target for the pancreatic carcinoma. Activation of RXRα has a synergic action with PPARγ agonist on the growth inhibition of pancreatic carcinoma.