Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death
Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death
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DOI：
10.1038/sj.neo.7900050
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发表时间：
1999-10-01
期刊：
影响因子：
--
通讯作者：
Breyer, Matthew D.
中科院分区：
文献类型：
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作者：
Guan, You-Fei;Zhang, Ya-Hua;Breyer, Matthew D.
本研究探讨了噻唑烷二酮（TZD）激活的转录因子，过氧化物酶体增殖体激活受体γ (PPARgamma)在人类膀胱癌中的表达和作用。原位杂交显示PPARgamma mRNA在所有研究的人类移行上皮细胞癌（TCCa's）中高度表达（n=11）。通过RNase保护实验和免疫印迹检测，PPARgamma也在5种TCCa细胞系中表达。视黄醇X受体α (rxrα)是PPARgamma的9-顺式维甲酸刺激（9-顺式ra）异二聚体伴侣，也在所有TCCa组织和细胞系中共表达。用TZD PPARgamma激动剂曲格列酮治疗T24膀胱癌细胞，可显著抑制3h -胸腺嘧啶掺入并诱导细胞死亡。rxrα配体9-顺式ra或LG100268的加入使T24膀胱癌细胞对曲格列酮和另外两种PPARgamma激活剂西格列酮和15-脱氧- delta12,14 - pgj2 （15dPGJ2）的致死作用增敏。曲格列酮治疗增加了两种细胞周期蛋白依赖性激酶抑制剂p21WAF1/CIP1和p16INK4的表达，降低了细胞周期蛋白D1的表达，与G1停止一致。曲格列酮还诱导了T24细胞内源性PPARgamma靶基因脂肪细胞型脂肪酸结合蛋白（A-FABP）的表达，该基因的表达与膀胱癌分化相关。原位杂交显示A-FABP的表达局限于正常的尿上皮细胞和部分TCCa。综上所述，这些结果表明PPARgamma在人TCCa中表达，可能在调节TCCa分化和存活中发挥作用，从而为治疗尿上皮癌提供了一个潜在的靶点。
The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), in human bladder cancers. In situ hybridization shows that PPARgamma mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARgamma was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor alpha (RXRalpha), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARgamma, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARgamma agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRalpha ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPARgamma activators, ciglitazone and 15-deoxy-DELTA12,14-PGJ2 (15dPGJ2). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21WAF1/CIP1 and p16INK4, and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARgamma target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARgamma is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.