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. 2006 Apr 4;78(19):2249-54.
doi: 10.1016/j.lfs.2005.09.036. Epub 2005 Nov 11.

Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells

Hiromi Hagiwara  1 , Hiromi Sato, Sumiko Shirai, Shigeto Kobayashi, Keiko Fukumoto, Tatsuya Ishida, Taiichiro Seki, Toyohiko Ariga, Tomohiro Yano
Affiliations

Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells

Hiromi Hagiwara et al. Life Sci. .

Abstract

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-1 stimulated by hypoxia in a human metastatic RCC cell line, Caki-1 cells. Cx32 expression decreased both mRNA level and production of PAI-1, uPA and uPAR in Caki-1 cells. Cx32 also decreased hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha 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-2alpha 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-1alpha and HIF-2alpha gene expression and that Cx32 might suppress hypoxia-inducible gene expression under hypoxic conditions.

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