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Carcinogenesis Advance Access originally published online on June 26, 2008
Carcinogenesis 2008 29(10):1994-2000; doi:10.1093/carcin/bgn134
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

NSAIDs suppress the expression of claudin-2 to promote invasion activity of cancer cells

Shinji Mima, Masaya Takehara, Hiroko Takada, Tomoko Nishimura, Tatsuya Hoshino and Tohru Mizushima*

Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan

* To whom correspondence should be addressed. Tel/Fax: +81 96 371 4323; Email: mizu{at}gpo.kumamoto-u.ac.jp

Non-steroidal anti-inflammatory drugs (NSAIDs) show chemopreventive effects; however, the precise molecular mechanism of these effects is still unclear. On the other hand, the expression of proteins that form tight junctions (TJs) (such as claudins) in clinically isolated tumors is frequently altered relative to normal tissue. We previously reported that NSAIDs upregulate the expression of claudin-4 and that this upregulation contributes to NSAID-dependent inhibition of both migration activity and anchorage-independent growth of cancer cells. In the current study, we have systematically examined the effects of various NSAIDs on the expression of various TJ proteins and have found that NSAIDs specifically and drastically inhibit the expression of claudin-2. Overexpression or suppression of claudin-2 expression caused stimulation or inhibition, respectively, of the invasion and migration activity of cancer cells. Furthermore, NSAIDs inhibited the invasion and migration activity of cancer cells and this inhibition was suppressed by overexpression of claudin-2. In contrast, neither cell growth nor apoptosis induced by lack of anchorage of cancer cells was affected by overexpression or suppression of expression of claudin-2. These results suggest that inhibition of claudin-2 expression by NSAIDs contributes to NSAID-dependent inhibition of invasion of cancer cells in vitro and that it may be involved in the chemopreventive effects of NSAIDs by inhibiting metastasis in vivo.

Abbreviations: BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid; cDNA, complementary DNA; COX, cyclooxygenase; FBS, fetal bovine serum; MMP, matrix metalloproteinase; mRNA, messenger RNA; NSAID, non-steroidal anti-inflammatory drug; PCR, polymerase chain reaction; PG, prostaglandin; siRNA, small interfering RNA; TJ, tight junction

Received February 1, 2008; revised April 28, 2008; accepted May 27, 2008.


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