Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells
Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells
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DOI：
10.1016/j.lfs.2005.09.036
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发表时间：
2006-04-04
期刊：
影响因子：
6.1
通讯作者：
Yano, T
中科院分区：
文献类型：
--
作者：
Hagiwara, H;Sato, H;Yano, T
纤溶因子通过降解细胞外基质在肿瘤进展中发挥重要作用。尿激酶型纤溶酶原激活物(UPA)、uPA受体(UPAR)和1型纤溶酶原抑制物(PAI-1)在肾细胞癌(RCC)中的表达增加。缝隙连接蛋白(Cx)基因是缝隙连接基因中的一员，被认为是肿瘤抑制基因。我们已经报道，Cx32通过抑制Src依赖的信号通路来改善转移性肾癌细胞的恶性表型。在本研究中，我们检测了Cx32基因的表达对人转移性肾癌细胞系Caki-1细胞uPA、uPAR和PAI-1产生的影响，以及低氧刺激对PAI-I诱导的影响。Cx32的表达降低了Caki-1细胞PAI-I、uPA和uPAR的表达水平和产量。Cx32还可降低低氧诱导因子-1α和低氧诱导因子-2α的mRNA水平。Src抑制剂PP1可显著降低Caki-1细胞PAI-1、uPA、uPAR和HIF-α的mRNA水平。此外，Cx32抑制低氧条件下Caki-1细胞HIF-2a蛋白的表达。低氧条件下，Cx32转染组CAKI-1细胞PAI-1mRNA表达水平明显低于模型转染组。这些结果提示，Cx32可能通过抑制Src诱导的HIF-1α和HIF-2a基因表达而减少转移肾癌细胞PAI-1、uPA和uPAR的产生，并可能在低氧条件下抑制低氧诱导的基因表达。(C)2005 Elsevier Inc.保留所有权利。
Fibrinolytic factors have an important role in tumor progression through the degradation of extracellular matrix. The increased levels of urokinase-type plasminogen activator (uPA), uPA-receptor (uPAR) and type-1 PA inhibitor (PAI-1) are reported in human renal cell carcinoma (RCC). Connexin (Cx) gene, a member of gap junction, is known to act as a tumor suppressor gene. We have reported that Cx32 improves malignant phenotypes of metastatic RCC cells via the inhibition of Src-dependent signaling. In this study, we examined the effect of expression of Cx32 gene on the production of uPA, uPAR and PAI-1, and on the induction of PAI-I stimulated by hypoxia in a human metastatic RCC cell line, Caki-1 cells. Cx32 expression decreased both mRNA level and production of PAI-I, uPA and uPAR in Caki-1 cells. Cx32 also decreased hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha mRNA level. PP1, a Src inhibitor, significantly decreased PAI-1, uPA, uPAR and HIF-alpha mRNA levels in Caki-1 cells. Furthermore, Cx32 suppressed the induction of HIF-2a protein in Caki-1 cells under hypoxia. PAI-1 mRNA level in Cx32-transfected Caki-1 cells was lower than that of mock transfectant under hypoxic conditions. These results suggest that Cx32 might reduce PAI-1, uPA and uPAR production in metastatic RCC cells via the inhibition of Src-dependent induction of HIF-1 alpha and HIF-2a gene expression and that Cx32 might suppress hypoxia-inducible gene expression under hypoxic conditions. (c) 2005 Elsevier Inc. All rights reserved.