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The inhibitory effect of connexin 32 gene on metastasis in renal cell carcinoma
Author(s) -
Sato Hiromi,
Hagiwara Hiromi,
Senba Hironobu,
Fukumoto Keiko,
Nagashima Yoji,
Yamasaki Hiroshi,
Ueno Koichi,
Yano Tomohiro
Publication year - 2008
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20396
Subject(s) - connexin , biology , hypoxia (environmental) , cancer research , cell , metastasis , clone (java method) , renal cell carcinoma , cell culture , gene , gap junction , medicine , cancer , microbiology and biotechnology , intracellular , chemistry , genetics , organic chemistry , oxygen
We have previously reported that connexin (Cx) 32 gene, a member of gap junctions, was specifically downregulated in human renal cell carcinoma (RCC) and it acts as a tumor suppressor against RCC. Because there is no standard therapy for advanced RCC, we investigated the anti‐metastatic effect of Cx32 to seek a possibility of new RCC therapy. In this study, we used human metastatic RCC cell (Caki‐1), and established Cx32‐expressed cell clone (Caki‐1T) or only mock‐transfected cell clone (Caki‐1W). For experimental production of metastases, the cells were injected into the lateral tail vein of SCID mice. Seventy days after inoculation, metastatic colonies were observed in Caki‐1W inoculated group, though none of them were in Caki‐1T inoculated group. The plasma VEGF concentration was significantly lower in Caki‐1T group compared to Caki‐1W group. To investigate where Cx32 effects on, we also tried in vitro analysis and found that the malignant phenotypes involving metastasis steps were significantly decreased in Caki‐1T under hypoxia, a mimic condition of internal tumor environment. After hypoxia treatment, the protein level of HIF‐2α, which plays main role for hypoxia adaptation, was observed to increase in Caki‐1W, whereas no expression was observed in Caki‐1T. We investigated the activation of Src, which is required for stabilization of HIF‐2α, is suppressed in Caki‐1T compared to Caki‐1W. These results suggest that Cx32 inhibits hypoxia adaptation governed by HIF‐2α, and this may help to reduce the metastasis of RCC cells. © 2007 Wiley‐Liss, Inc.