Montuori Nunzia, Mattiello Amalia, Mancini Alessandro, Taglialatela Paola, Caputi Mario, Rossi Guido, Ragno Pia
Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Naples, Italy.
Int J Cancer. 2003 Jun 20;105(3):353-60. doi: 10.1002/ijc.11091.
The urokinase-type plasminogen activator (uPA) and its cellular receptor (uPAR) are involved in the proteolytic cascade required for tumor cell dissemination and metastasis, and are highly expressed in many human tumors. We have recently reported that uPA, independently of its enzymatic activity, is able to increase the expression of its own receptor in uPAR-transfected kidney cells at a posttranscriptional level. In fact, uPA, upon binding uPAR, modulates the activity and/or the level of a mRNA-stabilizing factor that binds the coding region of uPAR-mRNA. We now investigate the relevance of uPA-mediated posttranscriptional regulation of uPAR expression in non small cell lung carcinoma (NSCLC), in which the up-regulation of uPAR expression is a prognostic marker. We show that uPA is able to increase uPAR expression, both at protein and mRNA levels, in primary cell cultures obtained from tumor and adjacent normal lung tissues of patients affected by NSCLC, thus suggesting that the enzyme can exert its effect in lung cells. We investigated the relationship among the levels of uPA, uPAR and uPAR-mRNA binding protein(s) in NSCLC. Lung tissue analysis of 35 NSCLC patients shows an increase of both uPA and uPAR in tumor tissues, as compared to adjacent normal tissues, in 27 patients (77%); 19 of these 27 patients also show a parallel increase of the level and/or binding activity of a cellular protein capable of binding the coding region of uPAR-mRNA. Therefore, in tumor tissues, a strong correlation is observed among these 3 parameters, uPA, uPAR and the level and/or the activity of a uPAR-mRNA binding protein. We then suggest that uPA regulates uPAR expression in NSCLC at a posttranscriptional level by increasing uPAR-stability through a cellular factor that binds the coding region of uPAR-mRNA.
尿激酶型纤溶酶原激活剂（uPA）及其细胞受体（uPAR）参与肿瘤细胞扩散和转移所需的蛋白水解级联反应，且在许多人类肿瘤中高表达。我们最近报道，uPA与其酶活性无关，能够在转录后水平增加uPAR转染肾细胞中其自身受体的表达。事实上，uPA与uPAR结合后，会调节一种与uPAR - mRNA编码区结合的mRNA稳定因子的活性和/或水平。我们现在研究uPA介导的uPAR表达的转录后调控在非小细胞肺癌（NSCLC）中的相关性，其中uPAR表达上调是一个预后标志物。我们发现，在从NSCLC患者的肿瘤及相邻正常肺组织获得的原代细胞培养物中，uPA能够在蛋白质和mRNA水平上增加uPAR的表达，这表明该酶可在肺细胞中发挥作用。我们研究了NSCLC中uPA、uPAR和uPAR - mRNA结合蛋白水平之间的关系。对35例NSCLC患者的肺组织分析显示，与相邻正常组织相比，27例患者（77%）的肿瘤组织中uPA和uPAR均增加；这27例患者中有19例还显示出一种能够结合uPAR - mRNA编码区的细胞蛋白的水平和/或结合活性平行增加。因此，在肿瘤组织中，观察到这三个参数uPA、uPAR以及uPAR - mRNA结合蛋白的水平和/或活性之间存在很强的相关性。然后我们提出，uPA通过一种与uPAR - mRNA编码区结合的细胞因子增加uPAR的稳定性，从而在转录后水平调节NSCLC中uPAR的表达。
