File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
  • Find via Find It@HKUL
Supplementary

Conference Paper: Prostaglandin E receptors (EP2 and EP4) mediated NNK promoted gastric carcinogenesis

TitleProstaglandin E receptors (EP2 and EP4) mediated NNK promoted gastric carcinogenesis
Authors
KeywordsMedical sciences
Gastroenterology
Issue Date2009
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
Digestive Disease Week (DDW) 2009, Chicago, IL., 30 May-4 June 2009. In Gastroenterology, 2009, v. 136 n. 5, suppl. 1, p. A-616, abstract no. T1995 How to Cite?
AbstractBACKGROUND: Cigarette smoking is associated with various cancer deaths including gastric cancer. Ample evidence demonstrated that increased cumulative dose of cigarette smoke associated with increased risk of gastric cancer. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most important components in cigarette smoke contributes to gastric cancer development. However, the molecular mechanism by which NNK promotes gastric carcinogenesis is unclear. We have previously reported that nicotine promoted gastric cancer growth through cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway. AIM: This study aimed to examine the roles of PGE2 receptors (EP) in NNK promoted gastric cancer growth. Methods: Gastric cancer cell line MKN45 was cultured in presence or absence of NNK (10-100nM) treated with or without antagonists of EPs. Nude mice implanted with MNK-45 were used as human gastric cancer xenograft model. Cells were incubated with or without NNK for 24 hrs prior to subcutaneous injection into flank of mice. Cell growth was measured by [3H]-thymidine incorporation assay, cell proliferation by proliferating cell nuclear antigen, angiogenesis by von Willebrand factor and apoptosis by TUNEL. mRNA and protein levels were determined by real time RT-PCR and western blot respectively. RESULTS: Both In Vitro and In Vivo studies showed that NNK promoted cancer cell growth concomitant with COX-2/PGE2 upregulation. In cell line, mRNA levels of EP1-4 were constitutively expressed in basal condition, and NNK upregulated EP2 and EP4 expression but not EP1 and EP3. Such induction was significantly blunted by antagonists of EP2 (AH6809, 3uM) and EP4 (AH23848, 30uM). On the other hand, NNK (10-100nM) promoted tumor growth in a dose dependent manner In Vivo. Pretreatment with EP2 and EP4 antagonists repressed the tumor growth, concomitant with reduced cell proliferation, angiogenesis and increased apoptosis. Moreover, EP2 and EP4 antagonists reversed NNK induced tumorigenic properties through repression of PGE2, VEGF and VEGFR-2 levels. VEGFR inhibitor (CBOP11, 10uM) abrogated NNK-induced COX-2 and PGE2 levels, leading to retardation of cell proliferation. In addition, NNK caused upregulation of Bcl2, cyclin D1 and the associated cyclin-dependent kinase (CDK) 4/6, and downregulation of caspase-3, p21 and p27, which was abrogated by EP2 and EP4 antagonists. Conclusion: These data strongly indicate that EP2 and EP4 are important for NNK promoted gastric carcinogenesis. EP2 and EP4 antagonists therefore represent putative novel molecular targets for chemopreventive therapy or to inhibit gastric cancer growth for smokers.
DescriptionThis journal issue is the 2009 DDW Abstract Supplement
Persistent Identifierhttp://hdl.handle.net/10722/126998
ISSN
2015 Impact Factor: 18.187
2015 SCImago Journal Rankings: 7.170

 

DC FieldValueLanguage
dc.contributor.authorShin, VYen_HK
dc.contributor.authorJin, HCen_HK
dc.contributor.authorNg, EKOen_HK
dc.contributor.authorYu, Jen_HK
dc.contributor.authorCho, CHen_HK
dc.contributor.authorSung, JJYen_HK
dc.date.accessioned2010-10-31T13:00:31Z-
dc.date.available2010-10-31T13:00:31Z-
dc.date.issued2009en_HK
dc.identifier.citationDigestive Disease Week (DDW) 2009, Chicago, IL., 30 May-4 June 2009. In Gastroenterology, 2009, v. 136 n. 5, suppl. 1, p. A-616, abstract no. T1995en_HK
dc.identifier.issn0016-5085en_HK
dc.identifier.urihttp://hdl.handle.net/10722/126998-
dc.descriptionThis journal issue is the 2009 DDW Abstract Supplement-
dc.description.abstractBACKGROUND: Cigarette smoking is associated with various cancer deaths including gastric cancer. Ample evidence demonstrated that increased cumulative dose of cigarette smoke associated with increased risk of gastric cancer. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most important components in cigarette smoke contributes to gastric cancer development. However, the molecular mechanism by which NNK promotes gastric carcinogenesis is unclear. We have previously reported that nicotine promoted gastric cancer growth through cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway. AIM: This study aimed to examine the roles of PGE2 receptors (EP) in NNK promoted gastric cancer growth. Methods: Gastric cancer cell line MKN45 was cultured in presence or absence of NNK (10-100nM) treated with or without antagonists of EPs. Nude mice implanted with MNK-45 were used as human gastric cancer xenograft model. Cells were incubated with or without NNK for 24 hrs prior to subcutaneous injection into flank of mice. Cell growth was measured by [3H]-thymidine incorporation assay, cell proliferation by proliferating cell nuclear antigen, angiogenesis by von Willebrand factor and apoptosis by TUNEL. mRNA and protein levels were determined by real time RT-PCR and western blot respectively. RESULTS: Both In Vitro and In Vivo studies showed that NNK promoted cancer cell growth concomitant with COX-2/PGE2 upregulation. In cell line, mRNA levels of EP1-4 were constitutively expressed in basal condition, and NNK upregulated EP2 and EP4 expression but not EP1 and EP3. Such induction was significantly blunted by antagonists of EP2 (AH6809, 3uM) and EP4 (AH23848, 30uM). On the other hand, NNK (10-100nM) promoted tumor growth in a dose dependent manner In Vivo. Pretreatment with EP2 and EP4 antagonists repressed the tumor growth, concomitant with reduced cell proliferation, angiogenesis and increased apoptosis. Moreover, EP2 and EP4 antagonists reversed NNK induced tumorigenic properties through repression of PGE2, VEGF and VEGFR-2 levels. VEGFR inhibitor (CBOP11, 10uM) abrogated NNK-induced COX-2 and PGE2 levels, leading to retardation of cell proliferation. In addition, NNK caused upregulation of Bcl2, cyclin D1 and the associated cyclin-dependent kinase (CDK) 4/6, and downregulation of caspase-3, p21 and p27, which was abrogated by EP2 and EP4 antagonists. Conclusion: These data strongly indicate that EP2 and EP4 are important for NNK promoted gastric carcinogenesis. EP2 and EP4 antagonists therefore represent putative novel molecular targets for chemopreventive therapy or to inhibit gastric cancer growth for smokers.-
dc.languageengen_HK
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro-
dc.relation.ispartofGastroenterologyen_HK
dc.subjectMedical sciences-
dc.subjectGastroenterology-
dc.titleProstaglandin E receptors (EP2 and EP4) mediated NNK promoted gastric carcinogenesisen_HK
dc.typeConference_Paperen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0016-5085&volume=136&issue=5&spage=A616&epage=A616&date=2009&atitle=Prostaglandin+E+Receptors+(EP2+and+EP4)+Mediated+NNK+Promoted+Gastric+Carcinogenesisen_HK
dc.identifier.emailShin, VY: vyshin@hku.hken_HK
dc.identifier.emailNg, EKO: ngko@hku.hken_HK
dc.identifier.emailCho, CH: chcho@hku.hk-
dc.identifier.emailSung, JJY: joesung@cuhk.edu.hk-
dc.identifier.authorityNg, EKO=rp01364en_HK
dc.identifier.hkuros181439en_HK
dc.identifier.volume136en_HK
dc.identifier.issue5, suppl. 1en_HK
dc.identifier.spageA616en_HK
dc.identifier.epageA616en_HK
dc.publisher.placeUnited States-
dc.description.otherDigestive Disease Week (DDW) 2009, Chicago, IL., 30 May-4 June 2009. In Gastroenterology, 2009, v. 136 n. 5, suppl. 1, p. A-616, abstract no. T1995-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats