Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas
The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that the hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor sub...
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| Veröffentlicht in: | Carcinogenesis (New York) 2005-10, Vol.26 (10), p.1698-1705 |
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| creator | Ma, Xiaoli Chen, Kai Huang, Shuhong Zhang, Xiaoli Adegboyega, Patrick A. Evers, B.Mark Zhang, Hongwei Xie, Jingwu |
| description | The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that the hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor subtype is not well documented. Here, we report our findings that the elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 99 primary gastric cancers. Activation of the hedgehog pathway is associated with poorly differentiated and more aggressive tumors. The sonic hedgehog (Shh) transcript is localized to the cancer tissue, whereas expression of Gli1 and PTCH1 is observed both in the cancer and in the surrounding stroma. Treatment of gastric cancer cells with KAAD-cyclopamine, a hedgehog signaling inhibitor, decreases expression of Gli1 and PTCH1, resulting in cell growth inhibition and apoptosis. Overexpression of Gli1 under the control of the cytomegalovirus (CMV) promoter renders these cells resistant to cyclopamine-induced apoptosis. Thus, our analysis of in vivo tissues indicates that the hedgehog pathway is frequently activated in advanced gastric adenocarcinomas; our in vitro studies suggest that hedgehog signaling contributes to gastric cancer cell growth. These data predict that targeted inhibition of the hedgehog pathway may be effective in the prevention and treatment of advanced gastric adenocarcinomas. |
| doi_str_mv | 10.1093/carcin/bgi130 |
| format | Article |
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Recent studies indicate that the hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor subtype is not well documented. Here, we report our findings that the elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 99 primary gastric cancers. Activation of the hedgehog pathway is associated with poorly differentiated and more aggressive tumors. The sonic hedgehog (Shh) transcript is localized to the cancer tissue, whereas expression of Gli1 and PTCH1 is observed both in the cancer and in the surrounding stroma. Treatment of gastric cancer cells with KAAD-cyclopamine, a hedgehog signaling inhibitor, decreases expression of Gli1 and PTCH1, resulting in cell growth inhibition and apoptosis. Overexpression of Gli1 under the control of the cytomegalovirus (CMV) promoter renders these cells resistant to cyclopamine-induced apoptosis. Thus, our analysis of in vivo tissues indicates that the hedgehog pathway is frequently activated in advanced gastric adenocarcinomas; our in vitro studies suggest that hedgehog signaling contributes to gastric cancer cell growth. These data predict that targeted inhibition of the hedgehog pathway may be effective in the prevention and treatment of advanced gastric adenocarcinomas.</description><identifier>ISSN: 0143-3334</identifier><identifier>EISSN: 1460-2180</identifier><identifier>DOI: 10.1093/carcin/bgi130</identifier><identifier>PMID: 15905200</identifier><identifier>CODEN: CRNGDP</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; basal cell carcinoma ; BCC ; Biological and medical sciences ; Carcinogenesis, carcinogens and anticarcinogens ; CMV ; Cytomegalovirus ; Female ; Gene Expression Regulation, Neoplastic ; Hedgehog Proteins ; human patched gene 1 ; Humans ; In Situ Hybridization ; Male ; Medical sciences ; Neoplasm Staging ; Oncogene Proteins - genetics ; patched ; Patched Receptors ; Patched-1 Receptor ; PTC ; PTCH1 ; Receptors, Cell Surface - genetics ; Shh ; SMO ; smoothened ; sonic hedgehog ; Stomach Neoplasms - genetics ; Stomach Neoplasms - pathology ; Su(Fu) ; suppressor of fused ; Trans-Activators - genetics ; Transcription Factors - genetics ; Tumors ; Zinc Finger Protein GLI1</subject><ispartof>Carcinogenesis (New York), 2005-10, Vol.26 (10), p.1698-1705</ispartof><rights>2005 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Oct 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c522t-75d8a8fb933d9ce10f93063806ebf7f8f762d356fbd8529b403d610394c9c3953</citedby><cites>FETCH-LOGICAL-c522t-75d8a8fb933d9ce10f93063806ebf7f8f762d356fbd8529b403d610394c9c3953</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17175805$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15905200$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Xiaoli</creatorcontrib><creatorcontrib>Chen, Kai</creatorcontrib><creatorcontrib>Huang, Shuhong</creatorcontrib><creatorcontrib>Zhang, Xiaoli</creatorcontrib><creatorcontrib>Adegboyega, Patrick A.</creatorcontrib><creatorcontrib>Evers, B.Mark</creatorcontrib><creatorcontrib>Zhang, Hongwei</creatorcontrib><creatorcontrib>Xie, Jingwu</creatorcontrib><title>Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas</title><title>Carcinogenesis (New York)</title><addtitle>Carcinogenesis</addtitle><description>The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that the hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor subtype is not well documented. Here, we report our findings that the elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 99 primary gastric cancers. Activation of the hedgehog pathway is associated with poorly differentiated and more aggressive tumors. The sonic hedgehog (Shh) transcript is localized to the cancer tissue, whereas expression of Gli1 and PTCH1 is observed both in the cancer and in the surrounding stroma. Treatment of gastric cancer cells with KAAD-cyclopamine, a hedgehog signaling inhibitor, decreases expression of Gli1 and PTCH1, resulting in cell growth inhibition and apoptosis. Overexpression of Gli1 under the control of the cytomegalovirus (CMV) promoter renders these cells resistant to cyclopamine-induced apoptosis. Thus, our analysis of in vivo tissues indicates that the hedgehog pathway is frequently activated in advanced gastric adenocarcinomas; our in vitro studies suggest that hedgehog signaling contributes to gastric cancer cell growth. These data predict that targeted inhibition of the hedgehog pathway may be effective in the prevention and treatment of advanced gastric adenocarcinomas.</description><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>basal cell carcinoma</subject><subject>BCC</subject><subject>Biological and medical sciences</subject><subject>Carcinogenesis, carcinogens and anticarcinogens</subject><subject>CMV</subject><subject>Cytomegalovirus</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Hedgehog Proteins</subject><subject>human patched gene 1</subject><subject>Humans</subject><subject>In Situ Hybridization</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Neoplasm Staging</subject><subject>Oncogene Proteins - genetics</subject><subject>patched</subject><subject>Patched Receptors</subject><subject>Patched-1 Receptor</subject><subject>PTC</subject><subject>PTCH1</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Shh</subject><subject>SMO</subject><subject>smoothened</subject><subject>sonic hedgehog</subject><subject>Stomach Neoplasms - genetics</subject><subject>Stomach Neoplasms - pathology</subject><subject>Su(Fu)</subject><subject>suppressor of fused</subject><subject>Trans-Activators - genetics</subject><subject>Transcription Factors - genetics</subject><subject>Tumors</subject><subject>Zinc Finger Protein GLI1</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0M9rFDEUB_Agil2rR68yCHob-5I3ySRHLdbKFnvRIl5CJj92U3cn2yRb7X_vyCwueAokH16-70vISwrvKCg8sybbOJ4Nq0gRHpEF7QS0jEp4TBZAO2wRsTshz0q5BaACuXpKTihXwBnAglxfZH-392NtjK3x3tSYxiaFpq59s_Zu5ddp1exMXf8yD00cG-PuzWi9a1am1BztdOHHNIdIW1OekyfBbIp_cThPybeLj1_PL9ur60-fz99ftZYzVtueO2lkGBSiU9ZTCApBoAThh9AHGXrBHHIRBic5U0MH6AQFVJ1VFhXHU_J2nrvLacpfqt7GYv1mY0af9kUzkEiloBN8_R-8Tfs8Ttk0owqZ5Mgm1M7I5lRK9kHvctya_KAp6L8163lDPdc8-VeHofth691RH3qdwJsDMMWaTchTabEcXU97LoEfP46l-t__3k3-qUWPPdeX33_omy9LfrP8wPUS_wAoz5Xg</recordid><startdate>20051001</startdate><enddate>20051001</enddate><creator>Ma, Xiaoli</creator><creator>Chen, Kai</creator><creator>Huang, Shuhong</creator><creator>Zhang, Xiaoli</creator><creator>Adegboyega, Patrick A.</creator><creator>Evers, B.Mark</creator><creator>Zhang, Hongwei</creator><creator>Xie, Jingwu</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</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>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7U9</scope></search><sort><creationdate>20051001</creationdate><title>Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas</title><author>Ma, Xiaoli ; Chen, Kai ; Huang, Shuhong ; Zhang, Xiaoli ; Adegboyega, Patrick A. ; Evers, B.Mark ; Zhang, Hongwei ; Xie, Jingwu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c522t-75d8a8fb933d9ce10f93063806ebf7f8f762d356fbd8529b403d610394c9c3953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - pathology</topic><topic>basal cell carcinoma</topic><topic>BCC</topic><topic>Biological and medical sciences</topic><topic>Carcinogenesis, carcinogens and anticarcinogens</topic><topic>CMV</topic><topic>Cytomegalovirus</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Hedgehog Proteins</topic><topic>human patched gene 1</topic><topic>Humans</topic><topic>In Situ Hybridization</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Neoplasm Staging</topic><topic>Oncogene Proteins - genetics</topic><topic>patched</topic><topic>Patched Receptors</topic><topic>Patched-1 Receptor</topic><topic>PTC</topic><topic>PTCH1</topic><topic>Receptors, Cell Surface - genetics</topic><topic>Shh</topic><topic>SMO</topic><topic>smoothened</topic><topic>sonic hedgehog</topic><topic>Stomach Neoplasms - genetics</topic><topic>Stomach Neoplasms - pathology</topic><topic>Su(Fu)</topic><topic>suppressor of fused</topic><topic>Trans-Activators - genetics</topic><topic>Transcription Factors - genetics</topic><topic>Tumors</topic><topic>Zinc Finger Protein GLI1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Xiaoli</creatorcontrib><creatorcontrib>Chen, Kai</creatorcontrib><creatorcontrib>Huang, Shuhong</creatorcontrib><creatorcontrib>Zhang, Xiaoli</creatorcontrib><creatorcontrib>Adegboyega, Patrick A.</creatorcontrib><creatorcontrib>Evers, B.Mark</creatorcontrib><creatorcontrib>Zhang, Hongwei</creatorcontrib><creatorcontrib>Xie, Jingwu</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>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Virology and AIDS Abstracts</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Xiaoli</au><au>Chen, Kai</au><au>Huang, Shuhong</au><au>Zhang, Xiaoli</au><au>Adegboyega, Patrick A.</au><au>Evers, B.Mark</au><au>Zhang, Hongwei</au><au>Xie, Jingwu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2005-10-01</date><risdate>2005</risdate><volume>26</volume><issue>10</issue><spage>1698</spage><epage>1705</epage><pages>1698-1705</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><coden>CRNGDP</coden><abstract>The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that the hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor subtype is not well documented. Here, we report our findings that the elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 99 primary gastric cancers. Activation of the hedgehog pathway is associated with poorly differentiated and more aggressive tumors. The sonic hedgehog (Shh) transcript is localized to the cancer tissue, whereas expression of Gli1 and PTCH1 is observed both in the cancer and in the surrounding stroma. Treatment of gastric cancer cells with KAAD-cyclopamine, a hedgehog signaling inhibitor, decreases expression of Gli1 and PTCH1, resulting in cell growth inhibition and apoptosis. Overexpression of Gli1 under the control of the cytomegalovirus (CMV) promoter renders these cells resistant to cyclopamine-induced apoptosis. Thus, our analysis of in vivo tissues indicates that the hedgehog pathway is frequently activated in advanced gastric adenocarcinomas; our in vitro studies suggest that hedgehog signaling contributes to gastric cancer cell growth. These data predict that targeted inhibition of the hedgehog pathway may be effective in the prevention and treatment of advanced gastric adenocarcinomas.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>15905200</pmid><doi>10.1093/carcin/bgi130</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adenocarcinoma - genetics Adenocarcinoma - pathology basal cell carcinoma BCC Biological and medical sciences Carcinogenesis, carcinogens and anticarcinogens CMV Cytomegalovirus Female Gene Expression Regulation, Neoplastic Hedgehog Proteins human patched gene 1 Humans In Situ Hybridization Male Medical sciences Neoplasm Staging Oncogene Proteins - genetics patched Patched Receptors Patched-1 Receptor PTC PTCH1 Receptors, Cell Surface - genetics Shh SMO smoothened sonic hedgehog Stomach Neoplasms - genetics Stomach Neoplasms - pathology Su(Fu) suppressor of fused Trans-Activators - genetics Transcription Factors - genetics Tumors Zinc Finger Protein GLI1 |
| title | Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas |
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