Regulation of carcinoma cell invasion by protein C inhibitor whose expression is decreased in renal cell carcinoma
Regulation of carcinoma cell invasion by protein C inhibitor whose expression is decreased in renal cell carcinoma
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DOI：
10.1002/ijc.11594
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发表时间：
2004-02
影响因子：
6.4
通讯作者：
Toshiaki Wakita;Tatsuya Hayashi;J. Nishioka;H. Tamaru;N. Akita;K. Asanuma;H. Kamada;E. Gabazza;M. Ido;J. Kawamura;Koji Suzuki
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作者：
Toshiaki Wakita;Tatsuya Hayashi;J. Nishioka;H. Tamaru;N. Akita;K. Asanuma;H. Kamada;E. Gabazza;M. Ido;J. Kawamura;Koji Suzuki
蛋白C抑制物(PCI)是丝氨酸蛋白酶抑制物家族的成员，在人体的多种组织中都有产生，包括肝脏、肾脏和睾丸。除了抑制抗凝蛋白C途径外，经皮冠状动脉介入治疗还抑制尿纤溶酶原激活物(UPA)，uPA是一种众所周知的肿瘤细胞侵袭的介质。在本研究中，我们比较了人肾细胞癌(RCC)组织和非肿瘤肾组织中PCI的表达，以阐明其在肾脏中的生物学意义。在正常肾小管上皮细胞(RPTEC)中可检测到PCImRNA的表达，但在肾癌和肾癌细胞系(Caki-1细胞)中未见表达。非肿瘤肾和肾癌组织、RPTEC细胞和RPTEC来源的Caki-1细胞的pCI基因启动子区主要顺式元件的核苷酸序列没有差异。PCI表达载体对Caki-1细胞的体外侵袭能力明显低于未转染的Caki-1细胞，且可被抗pCI抗体阻断。由于PCI本身不影响体外培养的Caki-1细胞的增殖率，也不影响细胞uPA的表达，因此我们观察了uPA、PCI、热灭活的PCI和纤溶酶原激活物抑制物(PAI)-1对培养的RCC细胞侵袭能力的影响。表达uPA的Caki-1细胞体外侵袭力明显增强，且可被抗uPA抗体、pCI和PAI-1抑制，但不受热灭活pCI的抑制。此外，与空白对照组相比，pCI表达载体转染的Caki-1细胞培养上清液中uPA活性显著降低，uPA-pCI复合体水平显著升高。这些发现有力地表明，PCI通过抑制肾癌细胞分泌uPA来调节这些细胞的侵袭能力。我们的研究结果表明，经皮冠状动脉介入治疗可能是一种抑制肾肿瘤侵袭的潜在治疗药物。©2003 Wiley-Liss公司
Protein C inhibitor (PCI), a member of the serine protease inhibitor family, is produced in various human tissues, including the liver, kidney and testis. In addition to inhibiting the anticoagulant protein C pathway, PCI also inhibits urinary plasminogen activator (uPA), which is a well‐known mediator of tumor cell invasion. In the present study, to clarify the biologic significance of PCI in the kidney, we compared the expression of PCI between human renal cell carcinoma (RCC) tissue and nontumor kidney tissue. The PCI antigen level in RCC tissue was found to be significantly lower than in nontumor kidney tissue, and expression of PCI mRNA was detected in normal renal proximal tubular epithelial cells (RPTEC), but not in RCC or in an RCC cell line (Caki‐1 cells). No differences were detected between the nucleotide sequence of the major cis‐elements in the promoter region of the PCI gene from nontumor kidney and RCC tissues, RPTEC and Caki‐1 cells, an RPTEC‐derived RCC cell line. The in vitro invasiveness of Caki‐1 cells transfected with a PCI expression vector was significantly decreased compared to mock‐transfected Caki‐1 cells, and it was blocked in the presence of anti‐PCI antibody. Since PCI itself did not affect the proliferation rate of Caki‐1 cells or cell expression of uPA in vitro, the effect of uPA, PCI, heat‐inactivated PCI and plasminogen activator inhibitor (PAI)‐1 on the invasive potential of cultured RCC cells was evaluated. The in vitro invasiveness of Caki‐1 cells, which express uPA, was significantly enhanced by the addition of uPA, and it was inhibited by anti‐uPA antibody, PCI and PAI‐1, but not by heat‐inactivated PCI. In addition, uPA activity was significantly decreased and uPA‐PCI complex level was significantly increased in the culture medium of PCI expression vector‐transfected Caki‐1 cells as compared to mock‐transfected Caki‐1 cells. These findings strongly suggest that PCI regulates the invasive potential of RCC cells by inhibiting uPA secreted by these cells. The results of our study suggest that PCI might be a potential therapeutic agent for inhibiting renal tumor invasion. © 2003 Wiley‐Liss, Inc.