Guan Y F, Zhang Y H, Breyer R M, Davis L, Breyer M D
Division of Nephrology, Veterans Administration Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Neoplasia. 1999 Oct;1(4):330-9. doi: 10.1038/sj.neo.7900050.
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 PPAR- activators, ciglitazone and 15-deoxy-delta(12,14)-PGJ2 (15dPGJ(2)). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21(WAF1/CIP1) and p16(INK4), 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.
本研究检测了噻唑烷二酮（TZD）激活的转录因子过氧化物酶体增殖物激活受体γ（PPARγ）在人膀胱癌中的表达及作用。原位杂交显示，在所研究的所有人类移行上皮细胞癌（TCCa，n = 11）中PPARγ mRNA均高表达。通过核糖核酸酶保护分析和免疫印迹法确定，PPARγ在5种TCCa细胞系中也有表达。维甲酸X受体α（RXRα）是PPARγ的9-顺式维甲酸刺激的（9-cis-RA）异二聚体伴侣，在所有TCCa组织和细胞系中也共表达。用TZD PPARγ激动剂曲格列酮处理T24膀胱癌细胞，可显著抑制3H-胸腺嘧啶核苷掺入并诱导细胞死亡。添加RXRα配体9-顺式维甲酸或LG100268，可使T24膀胱癌细胞对曲格列酮以及另外两种PPAR激活剂环格列酮和15-脱氧-δ（12,14）-前列腺素J2（15dPGJ2）的致死作用敏感。曲格列酮处理可增加两种细胞周期蛋白依赖性激酶抑制剂p21（WAF1/CIP1）和p16（INK4）的表达，并降低细胞周期蛋白D1的表达，这与G1期阻滞一致。曲格列酮还可诱导T24细胞中内源性PPARγ靶基因脂肪细胞型脂肪酸结合蛋白（A-FABP）的表达，其表达与膀胱癌分化相关。原位杂交显示，A-FABP表达定位于正常尿路上皮细胞以及一些TCCa。综上所述，这些结果表明PPARγ在人TCCa中表达，它可能在调节TCCa分化和存活中发挥作用，从而为尿路上皮癌的治疗提供了一个潜在靶点。
