COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett’s oesophagus and oesophageal adenocarcinoma

Objectives:Bile reflux contributes to oesophageal injury and neoplasia. COX-2 is involved in both inflammation and carcinogenesis; however, the precise mechanisms by which bile acids promote COX-2 expression in the oesophagus are largely unknown. We analysed the molecular mechanisms that govern bile...

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Veröffentlicht in:Gut 2007-11, Vol.56 (11), p.1512-1521
Hauptverfasser: Song, Shumei, Guha, Sushovan, Liu, Kaifeng, Buttar, Navtej S, Bresalier, Robert S
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container_issue 11
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container_title Gut
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creator Song, Shumei
Guha, Sushovan
Liu, Kaifeng
Buttar, Navtej S
Bresalier, Robert S
description Objectives:Bile reflux contributes to oesophageal injury and neoplasia. COX-2 is involved in both inflammation and carcinogenesis; however, the precise mechanisms by which bile acids promote COX-2 expression in the oesophagus are largely unknown. We analysed the molecular mechanisms that govern bile acid-mediated expression of COX-2 in Barrett’s oesophagus and oesophageal adenocarcinoma (OA).Design:The effects of bile acids on COX-2 expression were analysed in immortalised Barrett’s oesophagus and OA cells using immunoblotting and transient transfections. Pharmacological inhibitors, phospho-specific antibodies, dominant-negative mutants and siRNA techniques were used to identify relevant signalling pathways. Flow cytometry and reactive oxygen species (ROS) scavengers were used to examine ROS involvement. Immunohistochemistry was performed on oesophageal mucosa obtained from an established rat model of bile reflux.Results:Unconjugated bile acids potently stimulated COX-2 expression and induced AKT and ERK1/2 phosphorylation in concert with COX-2 induction. These findings were mimicked in the in vivo rat model. Dominant-negative (DN) AKT and LY294002 (PI3K inhibitor) or U0126 (MEK-1/2 inhibitor) blocked chenodeoxycholic acid (CD) and deoxycholic acid (DC) mediated COX-2 induction. CD and DC also induced CREB phosphorylation and AP-1 activity. CREB-specific siRNA and DN AP-1 blocked CD and DC-induced COX-2 induction. Finally, CD and DC increased intracellular ROS, while ROS scavengers blocked COX-2 induction and the signalling pathways involved.Conclusions:Unconjugated bile acids induce CREB and AP-1-dependent COX-2 expression in Barrett’s oesophagus and OA through ROS-mediated activation of PI3K/AKT and ERK1/2. This study enhances our understanding of the molecular mechanisms by which bile acids promote the development of oesophageal adenocarcinoma.
doi_str_mv 10.1136/gut.2007.121244
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COX-2 is involved in both inflammation and carcinogenesis; however, the precise mechanisms by which bile acids promote COX-2 expression in the oesophagus are largely unknown. We analysed the molecular mechanisms that govern bile acid-mediated expression of COX-2 in Barrett’s oesophagus and oesophageal adenocarcinoma (OA).Design:The effects of bile acids on COX-2 expression were analysed in immortalised Barrett’s oesophagus and OA cells using immunoblotting and transient transfections. Pharmacological inhibitors, phospho-specific antibodies, dominant-negative mutants and siRNA techniques were used to identify relevant signalling pathways. Flow cytometry and reactive oxygen species (ROS) scavengers were used to examine ROS involvement. Immunohistochemistry was performed on oesophageal mucosa obtained from an established rat model of bile reflux.Results:Unconjugated bile acids potently stimulated COX-2 expression and induced AKT and ERK1/2 phosphorylation in concert with COX-2 induction. These findings were mimicked in the in vivo rat model. Dominant-negative (DN) AKT and LY294002 (PI3K inhibitor) or U0126 (MEK-1/2 inhibitor) blocked chenodeoxycholic acid (CD) and deoxycholic acid (DC) mediated COX-2 induction. CD and DC also induced CREB phosphorylation and AP-1 activity. CREB-specific siRNA and DN AP-1 blocked CD and DC-induced COX-2 induction. Finally, CD and DC increased intracellular ROS, while ROS scavengers blocked COX-2 induction and the signalling pathways involved.Conclusions:Unconjugated bile acids induce CREB and AP-1-dependent COX-2 expression in Barrett’s oesophagus and OA through ROS-mediated activation of PI3K/AKT and ERK1/2. This study enhances our understanding of the molecular mechanisms by which bile acids promote the development of oesophageal adenocarcinoma.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gut.2007.121244</identifier><identifier>PMID: 17604323</identifier><identifier>CODEN: GUTTAK</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>Acids ; Adenocarcinoma - etiology ; Adenocarcinoma - metabolism ; Adenocarcinoma - prevention &amp; control ; Animals ; Barrett Esophagus - etiology ; Barrett Esophagus - metabolism ; Bile ; Bile Acids and Salts - pharmacology ; Biological and medical sciences ; Cell Communication - physiology ; Cell Transformation, Neoplastic ; CREB-Binding Protein - metabolism ; Cyclooxygenase 2 - metabolism ; Esophageal Neoplasms - etiology ; Esophageal Neoplasms - metabolism ; Esophagus ; Gastroenterology. Liver. Pancreas. Abdomen ; Gastroesophageal Reflux - complications ; Humans ; Immunohistochemistry ; Kinases ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Medical sciences ; Mitogen-Activated Protein Kinase 3 - metabolism ; Oesophagus ; Other diseases. Semiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species - metabolism ; Rodents ; Studies ; Tumor Cells, Cultured</subject><ispartof>Gut, 2007-11, Vol.56 (11), p.1512-1521</ispartof><rights>2007 BMJ Publishing Group Ltd &amp; British Society of Gastroenterology</rights><rights>2007 INIST-CNRS</rights><rights>Copyright: 2007 2007 BMJ Publishing Group Ltd &amp; British Society of Gastroenterology</rights><rights>Copyright © 2007 BMJ Publishing Group &amp; British Society of Gastroenterology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b522t-c3d9ca656833360cf22579277557b6d38ee89d4b2fac9729e58cbd25231efb463</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttp://gut.bmj.com/content/56/11/1512.full.pdf$$EPDF$$P50$$Gbmj$$H</linktopdf><linktohtml>$$Uhttp://gut.bmj.com/content/56/11/1512.full$$EHTML$$P50$$Gbmj$$H</linktohtml><link.rule.ids>114,115,230,314,727,780,784,885,3196,23571,27924,27925,53791,53793,77600,77631</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=19153788$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17604323$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Shumei</creatorcontrib><creatorcontrib>Guha, Sushovan</creatorcontrib><creatorcontrib>Liu, Kaifeng</creatorcontrib><creatorcontrib>Buttar, Navtej S</creatorcontrib><creatorcontrib>Bresalier, Robert S</creatorcontrib><title>COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett’s oesophagus and oesophageal adenocarcinoma</title><title>Gut</title><addtitle>Gut</addtitle><description>Objectives:Bile reflux contributes to oesophageal injury and neoplasia. COX-2 is involved in both inflammation and carcinogenesis; however, the precise mechanisms by which bile acids promote COX-2 expression in the oesophagus are largely unknown. We analysed the molecular mechanisms that govern bile acid-mediated expression of COX-2 in Barrett’s oesophagus and oesophageal adenocarcinoma (OA).Design:The effects of bile acids on COX-2 expression were analysed in immortalised Barrett’s oesophagus and OA cells using immunoblotting and transient transfections. Pharmacological inhibitors, phospho-specific antibodies, dominant-negative mutants and siRNA techniques were used to identify relevant signalling pathways. Flow cytometry and reactive oxygen species (ROS) scavengers were used to examine ROS involvement. Immunohistochemistry was performed on oesophageal mucosa obtained from an established rat model of bile reflux.Results:Unconjugated bile acids potently stimulated COX-2 expression and induced AKT and ERK1/2 phosphorylation in concert with COX-2 induction. These findings were mimicked in the in vivo rat model. Dominant-negative (DN) AKT and LY294002 (PI3K inhibitor) or U0126 (MEK-1/2 inhibitor) blocked chenodeoxycholic acid (CD) and deoxycholic acid (DC) mediated COX-2 induction. CD and DC also induced CREB phosphorylation and AP-1 activity. CREB-specific siRNA and DN AP-1 blocked CD and DC-induced COX-2 induction. Finally, CD and DC increased intracellular ROS, while ROS scavengers blocked COX-2 induction and the signalling pathways involved.Conclusions:Unconjugated bile acids induce CREB and AP-1-dependent COX-2 expression in Barrett’s oesophagus and OA through ROS-mediated activation of PI3K/AKT and ERK1/2. This study enhances our understanding of the molecular mechanisms by which bile acids promote the development of oesophageal adenocarcinoma.</description><subject>Acids</subject><subject>Adenocarcinoma - etiology</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - prevention &amp; control</subject><subject>Animals</subject><subject>Barrett Esophagus - etiology</subject><subject>Barrett Esophagus - metabolism</subject><subject>Bile</subject><subject>Bile Acids and Salts - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Communication - physiology</subject><subject>Cell Transformation, Neoplastic</subject><subject>CREB-Binding Protein - metabolism</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Esophageal Neoplasms - etiology</subject><subject>Esophageal Neoplasms - metabolism</subject><subject>Esophagus</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gastroesophageal Reflux - complications</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Kinases</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Medical sciences</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Oesophagus</subject><subject>Other diseases. Semiology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Rodents</subject><subject>Studies</subject><subject>Tumor Cells, Cultured</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFkcuO0zAUhiMEYsrAmh2yhNggpeNL4ssGaYiAQYwYIS5iZ504TuqS2sVOynTHa7Dk1XgSUlp1YMXq6Oh8_3-O_WfZQ4LnhDB-1o3DnGIs5oQSWhS3shkpuMwZlfJ2NsOYiLwUhTrJ7qW0xBhLqcjd7IQIjgtG2Sz7WV19zilyvhnN4IJH9RaN3gS_HDsYbINq11sExjVpgjah39iEooUJ3lgUrred9SitrXE25SvbuD-i5DoPfe98h9YwLL7BdqdGzyFGOwy_vv9IKNgU1gvoxoTAN8fWQo-gsT4YiMb5sIL72Z0W-mQfHOpp9vHliw_VRX559ep1dX6Z1yWlQ25YowzwkkvGGMempbQUigpRlqLmDZPWStUUNW3BKEGVLaWpG1pSRmxbF5ydZs_2vuuxnh5irB8i9Hod3QriVgdw-t-JdwvdhY2mWJW8IJPB44NBDF9Hmwa9DGOc_iFpIoRiBVFCTtTZnjIxpBRte9xAsN5lqqdM9S5Tvc90Ujz6-7Ab_hDiBDw5AJAM9G0Eb1y64RQpmZC71fmec2mw18c5xC-aCyZK_fZTpauCv3tzgal-P_FP93y9Wv73yt86S8vZ</recordid><startdate>20071101</startdate><enddate>20071101</enddate><creator>Song, Shumei</creator><creator>Guha, Sushovan</creator><creator>Liu, Kaifeng</creator><creator>Buttar, Navtej S</creator><creator>Bresalier, Robert S</creator><general>BMJ Publishing Group Ltd and British Society of Gastroenterology</general><general>BMJ</general><general>BMJ Publishing Group LTD</general><general>BMJ Group</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20071101</creationdate><title>COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett’s oesophagus and oesophageal adenocarcinoma</title><author>Song, Shumei ; Guha, Sushovan ; Liu, Kaifeng ; Buttar, Navtej S ; Bresalier, Robert S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b522t-c3d9ca656833360cf22579277557b6d38ee89d4b2fac9729e58cbd25231efb463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Acids</topic><topic>Adenocarcinoma - etiology</topic><topic>Adenocarcinoma - metabolism</topic><topic>Adenocarcinoma - prevention &amp; control</topic><topic>Animals</topic><topic>Barrett Esophagus - etiology</topic><topic>Barrett Esophagus - metabolism</topic><topic>Bile</topic><topic>Bile Acids and Salts - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Communication - physiology</topic><topic>Cell Transformation, Neoplastic</topic><topic>CREB-Binding Protein - metabolism</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Esophageal Neoplasms - etiology</topic><topic>Esophageal Neoplasms - metabolism</topic><topic>Esophagus</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gastroesophageal Reflux - complications</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Kinases</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Medical sciences</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Oesophagus</topic><topic>Other diseases. Semiology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Rodents</topic><topic>Studies</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Song, Shumei</creatorcontrib><creatorcontrib>Guha, Sushovan</creatorcontrib><creatorcontrib>Liu, Kaifeng</creatorcontrib><creatorcontrib>Buttar, Navtej S</creatorcontrib><creatorcontrib>Bresalier, Robert S</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Science Journals</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Shumei</au><au>Guha, Sushovan</au><au>Liu, Kaifeng</au><au>Buttar, Navtej S</au><au>Bresalier, Robert S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett’s oesophagus and oesophageal adenocarcinoma</atitle><jtitle>Gut</jtitle><addtitle>Gut</addtitle><date>2007-11-01</date><risdate>2007</risdate><volume>56</volume><issue>11</issue><spage>1512</spage><epage>1521</epage><pages>1512-1521</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><coden>GUTTAK</coden><abstract>Objectives:Bile reflux contributes to oesophageal injury and neoplasia. COX-2 is involved in both inflammation and carcinogenesis; however, the precise mechanisms by which bile acids promote COX-2 expression in the oesophagus are largely unknown. We analysed the molecular mechanisms that govern bile acid-mediated expression of COX-2 in Barrett’s oesophagus and oesophageal adenocarcinoma (OA).Design:The effects of bile acids on COX-2 expression were analysed in immortalised Barrett’s oesophagus and OA cells using immunoblotting and transient transfections. Pharmacological inhibitors, phospho-specific antibodies, dominant-negative mutants and siRNA techniques were used to identify relevant signalling pathways. Flow cytometry and reactive oxygen species (ROS) scavengers were used to examine ROS involvement. Immunohistochemistry was performed on oesophageal mucosa obtained from an established rat model of bile reflux.Results:Unconjugated bile acids potently stimulated COX-2 expression and induced AKT and ERK1/2 phosphorylation in concert with COX-2 induction. These findings were mimicked in the in vivo rat model. Dominant-negative (DN) AKT and LY294002 (PI3K inhibitor) or U0126 (MEK-1/2 inhibitor) blocked chenodeoxycholic acid (CD) and deoxycholic acid (DC) mediated COX-2 induction. CD and DC also induced CREB phosphorylation and AP-1 activity. CREB-specific siRNA and DN AP-1 blocked CD and DC-induced COX-2 induction. Finally, CD and DC increased intracellular ROS, while ROS scavengers blocked COX-2 induction and the signalling pathways involved.Conclusions:Unconjugated bile acids induce CREB and AP-1-dependent COX-2 expression in Barrett’s oesophagus and OA through ROS-mediated activation of PI3K/AKT and ERK1/2. This study enhances our understanding of the molecular mechanisms by which bile acids promote the development of oesophageal adenocarcinoma.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><pmid>17604323</pmid><doi>10.1136/gut.2007.121244</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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subjects Acids
Adenocarcinoma - etiology
Adenocarcinoma - metabolism
Adenocarcinoma - prevention & control
Animals
Barrett Esophagus - etiology
Barrett Esophagus - metabolism
Bile
Bile Acids and Salts - pharmacology
Biological and medical sciences
Cell Communication - physiology
Cell Transformation, Neoplastic
CREB-Binding Protein - metabolism
Cyclooxygenase 2 - metabolism
Esophageal Neoplasms - etiology
Esophageal Neoplasms - metabolism
Esophagus
Gastroenterology. Liver. Pancreas. Abdomen
Gastroesophageal Reflux - complications
Humans
Immunohistochemistry
Kinases
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mitogen-Activated Protein Kinase 3 - metabolism
Oesophagus
Other diseases. Semiology
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species - metabolism
Rodents
Studies
Tumor Cells, Cultured
title COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett’s oesophagus and oesophageal adenocarcinoma
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