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Article: Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2

TitleNicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2
Authors
Issue Date2004
PublisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/
Citation
Carcinogenesis, 2004, v. 25 n. 12, p. 2487-2495 How to Cite?
AbstractEarly studies revealed that cigarette smoke promotes gastric cancer growth through the induction of cyclooxygenase-2 (COX-2). Nicotine, one of the active ingredients in cigarette smoke, has detrimental effects in the stomach. To date, there is no direct evidence to validate the effect of nicotine on gastric tumor growth and its carcinogenic mechanism(s). We therefore investigated whether nicotine could promote tumor growth and neovascularization in vivo, and the biological mechanism(s) in connection with the signaling cascade involving COX-2 and extracellular signal-regulated protein kinase (ERK). Athymic nude mice, with gastric cancer cells (AGS) orthotopically implanted into the gastric wall, treated with nicotine (50 or 200 μg/ml) in their drinking water for 3 months developed larger tumor areas than mice in the control group. Nicotine further increased proliferating cellular nuclear antigen (PCNA) staining and microvessel density by 70 and 30%, respectively, with concomitant activation of ERK phosphorylation, COX-2 and vascular endothelial growth factor (VEGF) expression in the tumors. Intraperitoneal administration of a selective COX-2 inhibitor (SC-236, 2 mg/kg) prevented the nicotine-induced tumor growth and neovascularization dose-dependently. Consistent with our animal model, an in vitro study also demonstrated that incubation with nicotine (50-200 μg/ml) for 5 h stimulated cell proliferation dose-dependently and increased COX-2 expression, prostaglandin E2 (PGE2) and VEGF release, as well as activation of ERK phosphorylation. Pre-treatment with specific mitogen-activated protein kinase kinase (MEK) inhibitors (U0126 or PD98059) attenuated COX-2 expression and subsequent PGE2 release by nicotine. Furthermore, the stimulatory action of nicotine on cancer cell growth and angiogenic factor VEGF production was suppressed by inhibitors of MEK (U0126) and COX-2 (SC-236). These findings reveal a direct promoting action of nicotine on the growth of gastric tumor and neovascularization through sequential activation of the ERK/COX-2/VEGF signaling pathway, which can be targeted for chemoprevention of gastric cancer, particularly in cigarette smokers. © Oxford University Press 2004; all rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/80334
ISSN
2015 Impact Factor: 4.874
2015 SCImago Journal Rankings: 2.439
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorShin, VYen_HK
dc.contributor.authorWu, WKKen_HK
dc.contributor.authorYe, YNen_HK
dc.contributor.authorSo, WHLen_HK
dc.contributor.authorKoo, MWLen_HK
dc.contributor.authorLiu, ESLen_HK
dc.contributor.authorLuo, JCen_HK
dc.contributor.authorCho, CHen_HK
dc.date.accessioned2010-09-06T08:05:09Z-
dc.date.available2010-09-06T08:05:09Z-
dc.date.issued2004en_HK
dc.identifier.citationCarcinogenesis, 2004, v. 25 n. 12, p. 2487-2495en_HK
dc.identifier.issn0143-3334en_HK
dc.identifier.urihttp://hdl.handle.net/10722/80334-
dc.description.abstractEarly studies revealed that cigarette smoke promotes gastric cancer growth through the induction of cyclooxygenase-2 (COX-2). Nicotine, one of the active ingredients in cigarette smoke, has detrimental effects in the stomach. To date, there is no direct evidence to validate the effect of nicotine on gastric tumor growth and its carcinogenic mechanism(s). We therefore investigated whether nicotine could promote tumor growth and neovascularization in vivo, and the biological mechanism(s) in connection with the signaling cascade involving COX-2 and extracellular signal-regulated protein kinase (ERK). Athymic nude mice, with gastric cancer cells (AGS) orthotopically implanted into the gastric wall, treated with nicotine (50 or 200 μg/ml) in their drinking water for 3 months developed larger tumor areas than mice in the control group. Nicotine further increased proliferating cellular nuclear antigen (PCNA) staining and microvessel density by 70 and 30%, respectively, with concomitant activation of ERK phosphorylation, COX-2 and vascular endothelial growth factor (VEGF) expression in the tumors. Intraperitoneal administration of a selective COX-2 inhibitor (SC-236, 2 mg/kg) prevented the nicotine-induced tumor growth and neovascularization dose-dependently. Consistent with our animal model, an in vitro study also demonstrated that incubation with nicotine (50-200 μg/ml) for 5 h stimulated cell proliferation dose-dependently and increased COX-2 expression, prostaglandin E2 (PGE2) and VEGF release, as well as activation of ERK phosphorylation. Pre-treatment with specific mitogen-activated protein kinase kinase (MEK) inhibitors (U0126 or PD98059) attenuated COX-2 expression and subsequent PGE2 release by nicotine. Furthermore, the stimulatory action of nicotine on cancer cell growth and angiogenic factor VEGF production was suppressed by inhibitors of MEK (U0126) and COX-2 (SC-236). These findings reveal a direct promoting action of nicotine on the growth of gastric tumor and neovascularization through sequential activation of the ERK/COX-2/VEGF signaling pathway, which can be targeted for chemoprevention of gastric cancer, particularly in cigarette smokers. © Oxford University Press 2004; all rights reserved.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/en_HK
dc.relation.ispartofCarcinogenesisen_HK
dc.rightsCarcinogenesis. Copyright © Oxford University Press.en_HK
dc.titleNicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0143-3334&volume=25 no 12&spage=2487&epage=2495&date=2004&atitle=Nicotine+promotes+gastric+tumor+growth+and+neovascularization+by+activating+extracellular+signal-regulated+kinase+and+cyclooxygenase-2en_HK
dc.identifier.emailKoo, MWL: wlkoo@hku.hken_HK
dc.identifier.authorityKoo, MWL=rp00233en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/carcin/bgh266en_HK
dc.identifier.pmid15319299-
dc.identifier.scopuseid_2-s2.0-10344240356en_HK
dc.identifier.hkuros97739en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-10344240356&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume25en_HK
dc.identifier.issue12en_HK
dc.identifier.spage2487en_HK
dc.identifier.epage2495en_HK
dc.identifier.isiWOS:000225531900025-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridShin, VY=7003491170en_HK
dc.identifier.scopusauthoridWu, WKK=18345422600en_HK
dc.identifier.scopusauthoridYe, YN=7401627402en_HK
dc.identifier.scopusauthoridSo, WHL=7004974020en_HK
dc.identifier.scopusauthoridKoo, MWL=7004550899en_HK
dc.identifier.scopusauthoridLiu, ESL=7202240071en_HK
dc.identifier.scopusauthoridLuo, JC=7404182407en_HK
dc.identifier.scopusauthoridCho, CH=7403100461en_HK
dc.identifier.citeulike60417-

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