Abstract | BACKGROUND AND PURPOSE: The connexin (Cx) 32 gene, a member of the gap junction gene family, acts as a tumour suppressor gene in human renal cell carcinoma (RCC) and is down-regulated by the hypermethylation of CpG islands in a promoter region of the Cx gene. The current study investigated whether the restoration of Cx32 silenced by hypermethylation in RCC by a DNA demethylating agent could be an effective treatment against RCC. EXPERIMENTAL APPROACH: Using nude mice bearing Caki-1 cells (a human metastatic RCC cell line), the effects of 5-aza-2'-deoxycytidine (5-aza-CdR), a DNA demethylase inhibitor, on Cx32 mRNA expression and tumour growth were examined by RT-PCR, and by measuring tumour weight and volume. Cx32 expression in Caki-1 tumours was inhibited by Cx32 short interfering (si) RNA, and the effect of siRNA on 5-aza-CdR-dependent suppression of tumour growth in nude mice was evaluated. KEY RESULTS: 5-aza-CdR treatment inhibited the growth of Caki-1 cells in nude mice by 70% and increased 7-fold the level of Cx32 mRNA. The intratumour injection of Cx32 siRNA almost totally inhibited the expression of Cx32 mRNA and significantly reduced the suppression of tumour growth in 5-aza-CdR-treated nude mice. CONCLUSIONS AND IMPLICATIONS: 5-aza-CdR suppressed the growth of Caki-1 tumours in a xenograft model, by restoring Cx32 expression. This finding suggests that treatment with 5-aza-CdR could be a new effective therapy against human metastatic RCC and that Cx32 could be a potential target for the treatment of RCC.
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Authors | H Hagiwara, H Sato, Y Ohde, Y Takano, T Seki, T Ariga, N Hokaiwado, M Asamoto, T Shirai, Y Nagashima, T Yano |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 153
Issue 7
Pg. 1373-81
(Apr 2008)
ISSN: 0007-1188 [Print] England |
PMID | 18264126
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites, Antineoplastic
- Connexins
- RNA, Messenger
- RNA, Small Interfering
- connexin 32
- Decitabine
- Azacitidine
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Topics |
- Animals
- Antimetabolites, Antineoplastic
(pharmacology)
- Azacitidine
(analogs & derivatives, pharmacology)
- Carcinoma, Renal Cell
(drug therapy, genetics)
- Cell Line, Tumor
- Connexins
(drug effects, genetics)
- Decitabine
- Female
- Humans
- Mice
- Mice, Nude
- RNA, Messenger
(drug effects, metabolism)
- RNA, Small Interfering
(pharmacology)
- Reverse Transcriptase Polymerase Chain Reaction
- Up-Regulation
(drug effects)
- Xenograft Model Antitumor Assays
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