Horvatić Herceg Gordana, Herceg Davorin, Kralik Marko, Bence-Zigman Zdenka, Tomić-Brzac Hrvojka, Kulić Ana
Clinical Department of Nuclear Medicine and Radiation Protection, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
Wien Klin Wochenschr. 2006 Oct;118(19-20):601-9. doi: 10.1007/s00508-006-0703-1.
Higher levels of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) are linked to the poor prognosis in a variety of malignances. uPA and PAI-1 were expressed in most thyroid carcinomas, as had been measured immunohistochemically. However, no relationship between their expression and clinicopathological parameters were found. Aim of the present study was to investigate the expression and clinical relevance of uPA and PAI-1 in thyroid cancer.
uPA and PAI-1 in paired cytosol samples of thyroid tumor and normal tissue were determined in 23 patients using enzyme-linked immunosorbent assay and correlated to the known prognostic features.
Both uPA and PAI-1 concentrations were significantly higher in malignant thyroid tumors (uPA=1.342 +/- 2.944 and PAI-1=17.615 +/- 31.933 ng/mg protein) than in normal tissue (uPA=0.002 +/- 0.009, P=0.011 and PAI-1=2.333 +/- 0.338 ng/mg protein, P=0.001) with positive correlation of the two proteins in the tumors. There were no differences in proteins' levels between benign tumors and normal tissue. Both proteins' concentrations were significantly different among various histological grades (uPA P=0.024 and PAI-1 P=0.017), showing higher values in higher tumor grades (grade I uPA=0.116 +/- 0.247 and PAI-1=4.802 +/- 4.151 ng/mg protein; grade III uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). The uPA and PAI-1 levels showed significant differences among different histological types of thyroid cancer (uPA P=0.049 and PAI-1=0.017). The lowest values were in adenomas (uPA=0.013 +/- 0.025 and PAI-1=2.785 +/- 1.069 ng/mg protein) and the highest in anaplastic carcinomas (uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). uPA and PAI-1 were significantly higher in anaplastic vs. well-differentiated cancers (uPA P=0.014 and PAI-1 P=0.026), if extrathyroidal invasion (uPA P=0.019 and PAI-1 P=0.009) or distant metastases (uPA P=0.006 and PAI-1 P=0.003) had been present, and in tumors whose size exceeded 1 cm in diameter (uPA P=0.009 and PAI-1 P=0.035). Only PAI-1, but not uPA was significantly higher in multicentric vs. solitary tumors (P=0.012) and lymph node positive compared to lymph node negative patients (P=0.042). The differences of uPA and PAI-1 did not reach the significant level when patients with well-differentiated tumors below and above 40 years of age had been compared. Survival analysis revealed the significant impact of both uPA and PAI-1 on the Progression-Free Survival (PFS) (38.84 vs. 3.67 months for patients with low and high uPA, respectively, P<0.001; 38.2 vs. 12 months for patients with low and high PAI-1, respectively, P=0.016).
The correlation of high uPA and PAI-1 with the known prognostic factors of poorer outcome and with lower PFS rate in patients with thyroid cancers proved that these proteins could be an additional prognostic parameter.
高水平的尿激酶型纤溶酶原激活剂（uPA）及其抑制剂（PAI-1）与多种恶性肿瘤的不良预后相关。免疫组化检测显示，大多数甲状腺癌中都有uPA和PAI-1表达。然而，未发现它们的表达与临床病理参数之间存在关联。本研究旨在探讨uPA和PAI-1在甲状腺癌中的表达及临床相关性。
采用酶联免疫吸附测定法，对23例患者甲状腺肿瘤及正常组织的配对胞浆样本中的uPA和PAI-1进行检测，并将其与已知的预后特征进行关联分析。
恶性甲状腺肿瘤中uPA和PAI-1的浓度（uPA = 1.342±2.944，PAI-1 = 17.615±31.933 ng/mg蛋白）均显著高于正常组织（uPA = 0.002±0.009，P = 0.011；PAI-1 = 2.333±0.338 ng/mg蛋白，P = 0.001），且肿瘤中这两种蛋白呈正相关。良性肿瘤与正常组织之间的蛋白水平无差异。不同组织学分级的肿瘤中，这两种蛋白的浓度均有显著差异（uPA P = 0.024，PAI-1 P = 0.017），肿瘤分级越高，其值越高（I级uPA = 0.116±0.247，PAI-1 = 4.802±4.151 ng/mg蛋白；III级uPA = 8.45±2.192，PAI-1 = 94.65±59.468 ng/mg蛋白）。甲状腺癌不同组织学类型之间，uPA和PAI-1水平存在显著差异（uPA P = 0.049，PAI-1 = 0.017）。最低值见于腺瘤（uPA = 0.013±0.025，PAI-1 = 2.785±1.069 ng/mg蛋白），最高值见于未分化癌（uPA = 8.45±2.192，PAI-1 = 94.65±59.468 ng/mg蛋白）。与高分化癌相比，未分化癌中的uPA和PAI-1显著更高（uPA P = 0.014，PAI-1 P = 0.026）；存在甲状腺外侵犯（uPA P = 0.019，PAI-1 P = 0.009）或远处转移（uPA P = 0.006，PAI-1 P = 0.003）的肿瘤，以及直径超过1 cm的肿瘤中，uPA和PAI-1也显著更高（uPA P = 0.009，PAI-1 P = 0.035）。多中心肿瘤与单中心肿瘤相比，仅PAI-1显著更高（P = 0.012）；有淋巴结转移的患者与无淋巴结转移的患者相比，PAI-1也显著更高（P = 0.042）。比较年龄在40岁以下和40岁以上的高分化肿瘤患者时，uPA和PAI-1的差异未达到显著水平。生存分析显示，uPA和PAI-1均对无进展生存期（PFS）有显著影响（uPA水平低和高的患者，PFS分别为38.84个月和3.67个月，P<0.001；PAI-1水平低和高的患者，PFS分别为38.2个月和12个月，P = 0.016）。
甲状腺癌患者中，高uPA和PAI-1与已知的预后较差的因素以及较低的PFS率相关，这证明这些蛋白可能是一个额外的预后参数。
