簇集蛋白赋予胰腺癌对吉西他滨的耐药性。

OBJECTIVE

To measure clusterin expression in pancreatic cancer tissues and cell lines and to evaluate whether clusterin confers resistance to gmcitabine in pancreatic cancer cells.

METHODS

Immunohistochemistry for clusterin was performed on 50 primary pancreatic cancer tissues and 25 matched backgrounds, and clusterin expression in 5 pancreatic cancer cell lines was quantified by Western blot and PT-PCR. The correlation between clusterin expression level and gmcitabine IC50 in pancreatic cancer cell lines was evaluated. The effect of an antisense oligonucleotide (ASO) against clusterin (ASO-CLU) [corrected] on gmcitabine resistance was evaluated by MTT assays. Xenograft model was used to demonstrate tumor growth.

RESULTS

Pancreatic cancer tissues expressed significantly higher levels of clusterin than did normal pancreatic tissues (P < 0.01). Clusterin expression levels were correlated with gmcitabine resistance in pancreatic cancer cell lines, and ASO-CLU [corrected] significantly decreased BxPc-3 cells resistance to gmcitabine (P < 0.01). In vivo systemic administration of AS clusterin and gmcitabine significantly decreased the s.c. BxPC-3 tumor volume compared with mismatch control ODN plus gmcitabine.

CONCLUSION

Our finding that clusterin expression was significantly higher in pancreatic cancer than in normal pancreatic tissues suggests that clusterin may confer gmcitabine resistance in pancreatic cancer cells.

目的

检测簇集蛋白在胰腺癌组织和细胞系中的表达，并评估其是否赋予胰腺癌细胞对吉西他滨的耐药性。

方法

对 50 例胰腺癌原发灶和 25 例配对癌旁组织进行簇集蛋白免疫组化染色，并用 Western blot 和 RT-PCR 方法定量检测 5 种胰腺癌细胞系中的簇集蛋白表达。评估胰腺癌细胞系中簇集蛋白表达水平与吉西他滨 IC50 的相关性。用 MTT 法评价针对簇集蛋白的反义寡核苷酸（ASO）[校正]对吉西他滨耐药性的影响。用异种移植模型证实肿瘤生长情况。

结果

胰腺癌组织中簇集蛋白的表达水平明显高于正常胰腺组织（P<0.01）。簇集蛋白的表达水平与胰腺癌细胞系对吉西他滨的耐药性相关，ASO-CLU[校正]显著降低了 BxPc-3 细胞对吉西他滨的耐药性（P<0.01）。体内系统给予 AS 簇集蛋白和吉西他滨显著降低了皮下接种的 BxPC-3 肿瘤体积，与错配对照寡核苷酸加吉西他滨相比。