Zheng Q, Tang Z Y, Xue Q, Shi D R, Song H Y, Tang H B
Department of General Surgery, Shanghai Sixth Municipal People Hospital, People's Republic of China.
J Cancer Res Clin Oncol. 2000 Nov;126(11):641-6. doi: 10.1007/s004320000146.
This study was designed to investigate the relationship of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor type-1 (PAI-1) to invasion and metastasis of hepatocellular carcinoma (HCC). The expression of uPA, uPAR, and PAI-1 in HCC was determined by immunohistochemistry, Northern blot, and an LCI-D20 nude mouse metastatic model of HCC. The overexpression of uPA, uPAR, and PAI-1 was found in HCC, especially in the patients with portal cancer embolus, tumor invasion, and metastasis. Immunohistochemistry results showed that the rate of positive staining of uPA, uPAR, and PAI-1 were higher in HCC than those in the control groups consisting of cancer-adjacent tissue and normal liver tissue. In the case of HCC invasion, positive uPA and uPAR were seen in 16 and 19 out of 22 patients, respectively (P<0.01 and P<0.001, respectively, as compared with the patients without invasion). In those with portal cancer embolus and tumor metastasis, positive uPAR was eight out of eight and six out of six patients. In those with tumor recurrence, positive uPAR was 15 out of 17 patients (P<0.01 vs. no recurrence). In patients who died within 2 years after surgery, positive uPAR was 12 out of 12 patients (P<0.01 vs. survival), and positive PAI-1 was nine out of 12 patients (P<0.05 vs. survival). In those in which uPA, uPAR, and PAI-1 were all positive staining, stronger cancer invasiveness and higher mortality were found (P<0.05 vs. patients with all negative staining). In 30 patients tested with Northern blot analysis, the results were similar to those tested with immunohistochemistry. Higher expression of uPA mRNA and PAI-1 mRNA were detected in tumor tissues and embolus. In the patients with positive signals of uPA mRNA and PAI-1 mRNA, invasive cases were found in seven out of 19 and eight out of 18 patients, respectively, which were significantly higher than those showing negative signals (P<0.05). In the LCI-D20 nude mouse metastatic model of HCC (MMHCC), PAI-1 activity in plasma and tumor tissue increased with tumor growth, invasion, and metastasis. At an advanced stage of MMHCC, PAI-1 activity rose to 15.4+/-0.7 Au/ml in plasma and 0.8+/-0.3 Au/mg in tumor extracts, which was significantly higher than 6.2+/-1.8 Au/ml in plasma and 0.4+/-0.1 Au/mg in extracts at an early stage (P<0.05). PAI-1 activity related to the changes of serum AFP and tumor progress were r = 0.9544 and r = 0.9648, respectively (P<0.05). The data suggest that the expression of uPA, uPAR, and PAI-1 is increased in HCC, and related to the invasiveness, metastasis, and prognosis of HCC.
本研究旨在探讨尿激酶型纤溶酶原激活剂（uPA）、uPA受体（uPAR）和纤溶酶原激活剂抑制剂1型（PAI-1）与肝细胞癌（HCC）侵袭和转移的关系。采用免疫组织化学、Northern印迹法以及HCC的LCI-D20裸鼠转移模型，检测HCC中uPA、uPAR和PAI-1的表达。结果发现HCC中uPA、uPAR和PAI-1均呈过表达，尤其在伴有门静脉癌栓、肿瘤侵袭和转移的患者中。免疫组织化学结果显示，HCC中uPA、uPAR和PAI-1的阳性染色率高于由癌旁组织和正常肝组织组成的对照组。在HCC侵袭患者中，22例患者中有16例和19例分别出现uPA和uPAR阳性（与无侵袭患者相比，P分别<0.01和P<0.001）。在伴有门静脉癌栓和肿瘤转移的患者中，8例患者中有8例、6例患者中有6例出现uPAR阳性。在肿瘤复发患者中，17例患者中有15例出现uPAR阳性（与未复发患者相比，P<0.01）。在术后2年内死亡的患者中，12例患者中有12例出现uPAR阳性（与存活患者相比，P<0.01），12例患者中有9例出现PAI-1阳性（与存活患者相比，P<0.05）。在uPA、uPAR和PAI-1均为阳性染色的患者中，发现更强的癌侵袭性和更高的死亡率（与所有染色均为阴性的患者相比，P<0.05）。在30例进行Northern印迹分析的患者中，结果与免疫组织化学检测结果相似。在肿瘤组织和栓子中检测到较高的uPA mRNA和PAI-1 mRNA表达。在uPA mRNA和PAI-1 mRNA呈阳性信号的患者中，19例患者中有7例、18例患者中有8例出现侵袭性病例，显著高于呈阴性信号的患者（P<0.05）。在HCC的LCI-D20裸鼠转移模型（MMHCC）中，血浆和肿瘤组织中的PAI-1活性随肿瘤生长、侵袭和转移而增加。在MMHCC晚期，血浆中PAI-1活性升至15.4±0.7 Au/ml，肿瘤提取物中为0.8±0.3 Au/mg，显著高于早期血浆中的6.2±1.8 Au/ml和提取物中的0.4±0.1 Au/mg（P<0.05）。PAI-1活性与血清AFP变化和肿瘤进展的相关性分别为r = 0.9544和r = 0.9648（P<0.05）。数据表明，HCC中uPA、uPAR和PAI-1的表达增加，且与HCC的侵袭性、转移及预后相关。
