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Cyclooxygenase-2 Inhibition suppresses ?vß6 integrin–dependent oral squamous carcinoma invasion

Cyclooxygenase-2 Inhibition suppresses ?vß6 integrin–dependent oral squamous carcinoma invasion
Cyclooxygenase-2 Inhibition suppresses ?vß6 integrin–dependent oral squamous carcinoma invasion
Worldwide oral squamous cell carcinoma (OSCC) represents about 5.5% of all malignancies, with ~30,000 new cases each year in the United States. The integrin ?vß6 and the enzyme cyclooxygenase-2 (COX-2) are implicated in OSCC progression and have been suggested as possible therapeutic targets. Each protein also is reported to identify dysplasias at high risk of malignant transformation, and current clinical trials are testing the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) at preventing OSCC development. Given the probable increased expression of ?vß6 and COX-2 in OSCC and the inhibition of several integrins by NSAIDs, we investigated whether NSAIDs affected ?vß6-dependent cell functions. We found that expression of both ?vß6 and COX-2 was significantly higher in OSCC compared with oral epithelial dysplasias. Neither protein preferentially identified those dysplastic lesions that became malignant. Using OSCC cell lines, modified to express varying levels of ?vß6, we assessed the effect of COX-2 inhibition on cell invasion. We found that the COX-2 inhibitor NS398 inhibited specifically ?vß6-dependent, but not ?vß6-independent, OSCC invasion in vitro and in vivo, and this effect was modulated through prostaglandin E2 (PGE2)–dependent activation of Rac-1. Transient expression of constitutively active Rac-1, or addition of the COX-2 metabolite PGE2, prevented the anti-invasive effect of NS398. Conversely, RNA interference down-regulation of Rac-1 inhibited ?vß6-dependent invasion. These findings suggest that COX-2 and ?vß6 interact in promoting OSCC invasion. This is a novel mechanism that, given the ubiquity of ?vß6 expression by head and neck cancers, raises the possibility that NSAIDs could protect against OSCC invasion.
0008-5472
10833-10842
Nystrom, Maria L.
d3ca00b3-f18c-46b5-9e8c-08ef34987015
McCullough, Diana
95beb545-66f0-4207-909a-bc72945d64e1
Weinreb, Paul H.
ba79e7c2-caf7-426e-a9e7-10b1ccc74e15
Violette, Shelia M.
9eb0cfe3-28f0-4319-ba2e-1fd84c43bf4b
Speight, Paul M.
2b6bfbdf-1114-4467-96e3-66acf4497ede
Marshall, John F.
1134b21f-7f23-4ee6-aaf5-c7580b73c10b
Hart, Ian R.
6a3728fc-5385-4dd4-a5e3-edd5168a0e8d
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Nystrom, Maria L.
d3ca00b3-f18c-46b5-9e8c-08ef34987015
McCullough, Diana
95beb545-66f0-4207-909a-bc72945d64e1
Weinreb, Paul H.
ba79e7c2-caf7-426e-a9e7-10b1ccc74e15
Violette, Shelia M.
9eb0cfe3-28f0-4319-ba2e-1fd84c43bf4b
Speight, Paul M.
2b6bfbdf-1114-4467-96e3-66acf4497ede
Marshall, John F.
1134b21f-7f23-4ee6-aaf5-c7580b73c10b
Hart, Ian R.
6a3728fc-5385-4dd4-a5e3-edd5168a0e8d
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106

Nystrom, Maria L., McCullough, Diana, Weinreb, Paul H., Violette, Shelia M., Speight, Paul M., Marshall, John F., Hart, Ian R. and Thomas, Gareth J. (2006) Cyclooxygenase-2 Inhibition suppresses ?vß6 integrin–dependent oral squamous carcinoma invasion. Cancer Research, 66 (22), 10833-10842. (doi:10.1158/0008-5472.CAN-06-1640).

Record type: Article

Abstract

Worldwide oral squamous cell carcinoma (OSCC) represents about 5.5% of all malignancies, with ~30,000 new cases each year in the United States. The integrin ?vß6 and the enzyme cyclooxygenase-2 (COX-2) are implicated in OSCC progression and have been suggested as possible therapeutic targets. Each protein also is reported to identify dysplasias at high risk of malignant transformation, and current clinical trials are testing the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) at preventing OSCC development. Given the probable increased expression of ?vß6 and COX-2 in OSCC and the inhibition of several integrins by NSAIDs, we investigated whether NSAIDs affected ?vß6-dependent cell functions. We found that expression of both ?vß6 and COX-2 was significantly higher in OSCC compared with oral epithelial dysplasias. Neither protein preferentially identified those dysplastic lesions that became malignant. Using OSCC cell lines, modified to express varying levels of ?vß6, we assessed the effect of COX-2 inhibition on cell invasion. We found that the COX-2 inhibitor NS398 inhibited specifically ?vß6-dependent, but not ?vß6-independent, OSCC invasion in vitro and in vivo, and this effect was modulated through prostaglandin E2 (PGE2)–dependent activation of Rac-1. Transient expression of constitutively active Rac-1, or addition of the COX-2 metabolite PGE2, prevented the anti-invasive effect of NS398. Conversely, RNA interference down-regulation of Rac-1 inhibited ?vß6-dependent invasion. These findings suggest that COX-2 and ?vß6 interact in promoting OSCC invasion. This is a novel mechanism that, given the ubiquity of ?vß6 expression by head and neck cancers, raises the possibility that NSAIDs could protect against OSCC invasion.

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Published date: 15 November 2006

Identifiers

Local EPrints ID: 66687
URI: http://eprints.soton.ac.uk/id/eprint/66687
ISSN: 0008-5472
PURE UUID: b0dbef3a-8210-4c81-8852-3e958bb08653

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Date deposited: 10 Jul 2009
Last modified: 13 Mar 2024 18:30

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Contributors

Author: Maria L. Nystrom
Author: Diana McCullough
Author: Paul H. Weinreb
Author: Shelia M. Violette
Author: Paul M. Speight
Author: John F. Marshall
Author: Ian R. Hart

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