生长因子及尿激酶型纤溶酶原激活物系统在胰腺导管腺癌中的预后意义

Prognostic significance of growth factors and the urokinase-type plasminogen activator system in pancreatic ductal adenocarcinoma.

作者信息

Xue Aiqun, Scarlett Christopher J, Jackson Christopher J, Allen Barry J, Smith Ross C

机构信息

Department of Surgery, The University of Sydney, Sydney, Australia.

出版信息

Pancreas. 2008 Mar;36(2):160-7. doi: 10.1097/MPA.0b013e31815750f0.

DOI:10.1097/MPA.0b013e31815750f0

PMID:18376307

Abstract

OBJECTIVES

To determine the diagnostic and prognostic significance of growth factors and the urokinase-type plasminogen activator (uPA) system in pancreatic ductal adenocarcinoma (PDAC) using a multigene assay.

METHODS

Messenger RNA (mRNA) expression of 15 genes from epidermal growth factor receptor, insulin-like growth factor (IGF), and uPA families were measured in 46 PDAC tissue samples using quantitative real-time reverse transcription-polymerase chain reaction. These results were compared with those of the uninvolved adjacent (AP) tissue and benign mucinous cystadenomas (BMC). The mRNA expression was evaluated using logistic regression and receiver operating characteristic area under the curve (ROC AUC) analyses. Their relationship with prognosis was tested by Cox regression multivariate analysis.

RESULTS

All genes were overexpressed in most of the PDAC tissue. When compared with AP tissue, the median expression values for IGF-binding protein 3 (IGFBP-3) and uPA receptor (uPAR) was 9.8- and 9.6-fold, respectively. Expression levels of uPA, uPAR, IGF-I, and IGFBP-3 mRNA were significantly greater in PDAC than in BMC. The IGFBP-3 mRNA expression demonstrated greatest ROC AUC values for PDAC versus AP tissue (ROC AUC, 0.745; 95% confidence interval [CI], 0.65-0.86); whereas ROC AUC values were greatest for uPAR when PDAC was compared with BMC (ROC AUC, 0.846; 95% CI, 0.76-0.94). The combination of uPA, uPAR, and IGF-I significantly improved discriminatory power (ROC AUC, 0.965; 95% CI, 0.93-1.00). The IGFBP-3, uPA, plasminogen activator inhibitor-2, and International Union Against Cancer stage had a significant influence on survival, but the effect of IGFBP-3 was lost after multivariate stepwise analysis.

CONCLUSIONS

These results indicate that there is an influence of IGF system in tumor progression from BMC to PDAC, whereas the uPA/uPAR system has the greater influence on survival in PDAC.

摘要

目的

使用多基因检测确定生长因子和尿激酶型纤溶酶原激活剂（uPA）系统在胰腺导管腺癌（PDAC）中的诊断和预后意义。

方法

使用定量实时逆转录聚合酶链反应在46例PDAC组织样本中检测来自表皮生长因子受体、胰岛素样生长因子（IGF）和uPA家族的15个基因的信使核糖核酸（mRNA）表达。将这些结果与未受累的相邻（AP）组织和良性黏液性囊腺瘤（BMC）的结果进行比较。使用逻辑回归和曲线下受试者工作特征面积（ROC AUC）分析评估mRNA表达。通过Cox回归多变量分析测试它们与预后的关系。

结果

所有基因在大多数PDAC组织中均过度表达。与AP组织相比，胰岛素样生长因子结合蛋白3（IGFBP-3）和uPA受体（uPAR）的中位表达值分别为9.8倍和9.6倍。PDAC中uPA、uPAR、IGF-I和IGFBP-3 mRNA的表达水平显著高于BMC。IGFBP-3 mRNA表达在PDAC与AP组织的比较中显示出最大的ROC AUC值（ROC AUC，0.745；95%置信区间[CI]，0.65 - 0.86）；而在PDAC与BMC比较时，uPAR的ROC AUC值最大（ROC AUC，0.846；95% CI，0.76 - 0.94）。uPA、uPAR和IGF-I的组合显著提高了鉴别能力（ROC AUC，0.965；95% CI，0.93 - 1.00）。IGFBP-3、uPA、纤溶酶原激活剂抑制剂-2和国际抗癌联盟分期对生存有显著影响，但在多变量逐步分析后IGFBP-3的影响消失。