Identification of cisplatin-resistant gene in bladder cancer by DNA chip

我们研究了顺铂对胚胎癌(EC)的诱导分化和克服顺铂耐药。以人TTSC-3细胞系移植于裸鼠体内为靶点。TTSC-3荷瘤小鼠腹腔注射顺铂1 mg/kg/周后，观察肿瘤组织病理变化，应用基因芯片技术检测肿瘤组织中各种基因的表达，发现小剂量顺铂对肿瘤生长无影响。然而，每周注射顺铂5 mg/kg可使肿瘤显著消退。相比之下，顺铂3 mg/kg/周对肿瘤生长和诱导肿瘤休眠有一定的抑制作用。组织学检查显示，注射顺铂可诱导EC分化。比较顺铂和生理盐水处理10周的TTSC-3细胞反转录mRNAs中差异表达的基因，发现在顺铂处理的TTSC-3细胞中，与细胞凋亡相关的3个基因(肿瘤坏死因子受体1、caspase 8和Apaf1)在1176个差异表达基因中与生理盐水注射相比显著增加。本研究表明，中剂量顺铂通过诱导分化和增强细胞凋亡相关基因的表达来抑制EC的生长。在另一项研究中，我们还发现联合应用TRAIL和顺铂可以克服顺铂耐药。这些发现支持TRAIL联合顺铂在体内治疗顺铂耐药膀胱癌的潜在应用。

We investigated the differentiation of embryonal carcinoma (EC) by cisplatin and overcoming cisplatin-resistance. The TTSC-3 human EC line heterotransplanted in nude mice was used as targets. After treatment of tumor-bearing mice with intraperitoneal injections of cisplatin, histopathological examination was assessed and various gene expressions in the tumors was determined by cDNA array technology, When cisplatin at 1 mg/kg/week was injected intraperitoneally into TTSC-3-bearing mice, the low dose cisplatin had no effect on tumor growth. However, injection of cisplatin at 5 mg/kg/week induced marked regression of the tumor. In contrast, cisplatin at 3 mg/kg/week had a modest inhibitory effect on tumor growth and induced tumor dormancy. Histological examination revealed that injection of cisplatin induced differentiation of EC. cDNA probes from reverse transcribed mRNAs of TTSC-3 treated with cisplatin or saline for 10 weeks were compared to identify genes differentially expressed in cisplatin-treated TTSC-3, Of 1176 different human cDNA transcripts in cisplatin-treated TTSC-3, three genes (tumor necrosis factor receptor 1, caspase 8 and Apaf1), which are associated with apoptosis, were found to be markedly increased, compared to saline injection. The present study demonstrates that intermediate dose of cisplatin inhibited tumor growth of EC by induction of differentiation and enhancement of the apoptosis-related gene expressions.In the other study, we have shown that combination treatment of baldder cancer cells with TRAIL and cisplatin overcomes cisplatin-resistance. These findings support the potential application in vivo of a combination of TRAIL and cisplatin in the treatment of cisplatin-resistant bladder cancer.