Smith Ross, Xue AiQun, Gill Anthony, Scarlett Christopher, Saxby Alexander, Clarkson Adele, Hugh Thomas
Department of Surgery, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW, Australia.
World J Surg. 2007 Mar;31(3):493-502; discussion 503. doi: 10.1007/s00268-006-0289-9.
Recent findings suggest that the urokinase-type plasminogen activator (uPA), its receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and -2 (PAI-2) play key roles in cancer invasion. The prognostic value of components of this system is well established in breast cancer. However, little is known of its involvement in pancreatic cancer (PC).
Quantitative real-time polymerase chain reaction (Q-RT-PCR) was used on tissue-banked specimens and immunohistochemistry (IHC) on paraffin specimens was used to measure expression of uPA, uPAR, PAI-1, and PAI-2 proteins in 46 PC and 12 cystadenoma specimens. Results were related to survival using Cox's proportional hazards testing.
Increased expression of uPA, uPAR, and PAI-1 in PC tissue were independently associated with a higher Union Internationale Contre le Cancer [International Union Against Cancer (UICC)] tumor stage (P < 0.001) and were intercorrelated (P < 0.001). Overexpression of uPAR indicated reduced survival (P = 0.03). Conversely, PAI-2 messenger ribonucleic acid (mRNA) overexpression, which occurred in 21 of 46 tumors, negatively correlated with tumor size (P = 0.008) and survival (P < 0.007) but not with uPA, uPAR, or tumor stage. There was good agreement between PAI-2 mRNA value and IHC score (P < 0.001). Using Cox's stepwise analysis, PAI-2 mRNA value (HR = 0.24; P = 0.001) and UICC tumor stage (HR = 2.014; P = 0.001) independently predicted survival. An IHC score for PAI-2 of 3+ or 4+ also independently predicted improved survival (HR = 2.72; P = 0.025).
The uPA/uPAR/PAI-1 system is activated in advanced pancreatic cancer and may account for the tumor's aggressive behavior, whereas PAI-2 expression appears to be independent of uPA/uPAR/PAI-1 and is associated with improved prognosis. Because of its intercorrelation with mRNA expression, PAI-2 IHC may be used as an indicator of survival.
近期研究结果表明，尿激酶型纤溶酶原激活剂（uPA）、其受体（uPAR）、纤溶酶原激活剂抑制剂-1（PAI-1）和-2（PAI-2）在癌症侵袭中起关键作用。该系统各成分在乳腺癌中的预后价值已得到充分证实。然而，其在胰腺癌（PC）中的作用却鲜为人知。
对存档组织标本进行定量实时聚合酶链反应（Q-RT-PCR），并对石蜡标本进行免疫组织化学（IHC）检测，以测量46例PC和12例囊腺瘤标本中uPA、uPAR、PAI-1和PAI-2蛋白的表达。使用Cox比例风险检验将结果与生存率相关联。
PC组织中uPA、uPAR和PAI-1表达增加与较高的国际抗癌联盟（UICC）肿瘤分期独立相关（P < 0.001），且相互关联（P < 0.001）。uPAR过表达表明生存率降低（P = 0.03）。相反，46例肿瘤中有21例出现PAI-2信使核糖核酸（mRNA）过表达，其与肿瘤大小（P = 0.008）和生存率（P < 0.007）呈负相关，但与uPA、uPAR或肿瘤分期无关。PAI-2 mRNA值与IHC评分之间具有良好的一致性（P < 0.001）。使用Cox逐步分析，PAI-2 mRNA值（HR = 0.24；P = 0.001）和UICC肿瘤分期（HR = 2.014；P = 0.001）独立预测生存率。PAI-2的IHC评分为3+或4+也独立预测生存率提高（HR = 2.72；P = 0.025）。
uPA/uPAR/PAI-1系统在晚期胰腺癌中被激活，可能是肿瘤侵袭性行为的原因，而PAI-2表达似乎独立于uPA/uPAR/PAI-1，且与预后改善相关。由于PAI-2 IHC与mRNA表达相互关联，它可作为生存率的指标。
