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Identification of Drug Resistance Gene by Microarray and Elucidation of Mechanism of Drug Resistance in Urogenital Cancer

泌尿生殖系统肿瘤耐药基因的微阵列鉴定及耐药机制的阐明

基本信息

批准号：
14571506
负责人：
KOGA Hirofumi
金额：
$ 2.5万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571506/
关键词：
urogenital cancer cisplatin drug resistance microarray bladder cancer IP3R1 MDR1 MRP IP_3R1 耐性遺伝子抗癌剤薬剤耐性耐性克服

项目摘要

1.To investigate the molecules that regulate the acquisition of cisplatin resistance, we performed cDNA microarrays using two pairs of parental and cisplatin-resistant bladder cancer cell lines. We found a markedly reduced expression of inositol 1,4,5-trisphosphate receptor typel (IP3R1), endoplasmic reticulum membrane protein, in cisplatin-resistant cells. The suppression of IP3R1 expression using small interfering RNA in parental cells prevented apoptosis and resulted in decreased sensitivity to cisplatin. Contrarily, overexpression of IP3R1 in resistant cells induced apoptosis and increased sensitivity to cisplatin. These results suggest that cisplatin-induced downregulation of IP3R1 expression was closely associated with the acquisition of cisplatin resistance in bladder cancer cells.2.Overexpression of the P-glycoprotein/multidrug resistance 1(MDR1) and multidrug resistance-associated protein(MRP) gene is associated with drug resistance to some chemotherapeutic agents including doxorubicin. We determined the expressions of MDR1,MRP1,MRP2,and MRP3 gene in bladder cancer before and after the treatment using doxorubicin and investigated the correlation between the expressions of these genes and drug responses to doxorubicin. We showed that the each level of MDR1,MRP1,MRP2,and MRP3 gene expression after the treatment using doxorubicin was higher than that of gene expression before the treatment. We also found the significant correlation of MDR1,MRP1,and MRP3 mRNA levels with resistance to doxorubicin. These data suggest that MDR1,MRP1,and MRP3 mRNA levels were correlated with the response to doxorubicin.

1.为了研究调节顺铂耐药性获得的分子，我们使用两对亲本和顺铂耐药性膀胱癌细胞系进行了 cDNA 微阵列。我们发现顺铂耐药细胞中肌醇 1,4,5-三磷酸受体 1 型 (IP3R1)（内质网膜蛋白）的表达显着降低。在亲代细胞中使用小干扰 RNA 抑制 IP3R1 表达可防止细胞凋亡并导致对顺铂的敏感性降低。相反，耐药细胞中 IP3R1 的过度表达会诱导细胞凋亡并增加对顺铂的敏感性。这些结果提示顺铂诱导的IP3R1表达下调与膀胱癌细胞获得顺铂耐药密切相关。2.P-糖蛋白/多药耐药1（MDR1）和多药耐药相关蛋白（MRP）基因的过表达与阿霉素等化疗药物的耐药相关。我们测定了阿霉素治疗前后膀胱癌中MDR1、MRP1、MRP2和MRP3基因的表达，并研究了这些基因的表达与阿霉素药物反应之间的相关性。我们发现，使用阿霉素治疗后，MDR1、MRP1、MRP2 和 MRP3 基因表达水平均高于治疗前的基因表达水平。我们还发现 MDR1、MRP1 和 MRP3 mRNA 水平与阿霉素耐药性显着相关。这些数据表明 MDR1、MRP1 和 MRP3 mRNA 水平与阿霉素的反应相关。