Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β‐catenin/TCF
The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human orth...
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| Veröffentlicht in: | Cancer science 2008-06, Vol.99 (6), p.1139-1146 |
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| creator | Torisu, Yuichi Watanabe, Akira Nonaka, Aya Midorikawa, Yutaka Makuuchi, Masatoshi Shimamura, Takahiro Sugimura, Haruhiko Niida, Atsushi Akiyama, Tetsu Iwanari, Hiroko Kodama, Tatsuhiko Zeniya, Mikio Aburatani, Hiroyuki |
| description | The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of β‐catenin protein: all 10 HCC with high intracellular β‐catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular β‐catenin had high NOTUM expression (P |
| doi_str_mv | 10.1111/j.1349-7006.2008.00814.x |
| format | Article |
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In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of β‐catenin protein: all 10 HCC with high intracellular β‐catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular β‐catenin had high NOTUM expression (P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant‐negative mutant of TCF4, a β‐catenin partner. In vivo binding of the β‐catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of β‐catenin/TCF4 and is upregulated in Wnt/β‐catenin signaling‐activated HCC. (Cancer Sci 2008; 99: 1139–1146)</description><identifier>ISSN: 1347-9032</identifier><identifier>ISSN: 1349-7006</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/j.1349-7006.2008.00814.x</identifier><identifier>PMID: 18429952</identifier><language>eng</language><publisher>Melbourne, Australia: Blackwell Publishing Asia</publisher><subject>Adult ; Aged ; Animals ; Antibodies, Monoclonal ; beta Catenin - metabolism ; Biological and medical sciences ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Chromatin Immunoprecipitation ; Drosophila Proteins - genetics ; Drosophila Proteins - immunology ; Drosophila Proteins - metabolism ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Immunization ; Immunoblotting ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Mice ; Middle Aged ; Mutagenesis, Site-Directed ; Oligonucleotide Array Sequence Analysis ; Original /Report ; Promoter Regions, Genetic ; Rabbits ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - immunology ; Recombinant Fusion Proteins - metabolism ; Signal Transduction ; TCF Transcription Factors - genetics ; TCF Transcription Factors - metabolism ; Transcription Factor 7-Like 2 Protein ; Transcription, Genetic ; Tumor Cells, Cultured ; Tumors</subject><ispartof>Cancer science, 2008-06, Vol.99 (6), p.1139-1146</ispartof><rights>2008 Japanese Cancer Association</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5554-70777ff934d869d14ae489c8a2afb73ddc48f9ff628147f268dbca26504d2d293</citedby><cites>FETCH-LOGICAL-c5554-70777ff934d869d14ae489c8a2afb73ddc48f9ff628147f268dbca26504d2d293</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11158900/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11158900/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><linktorsrc>$$Uhttps://onlinelibrary.wiley.com/doi/abs/10.1111%2Fj.1349-7006.2008.00814.x$$EView_record_in_Wiley-Blackwell$$FView_record_in_$$GWiley-Blackwell</linktorsrc><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20389277$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18429952$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Torisu, Yuichi</creatorcontrib><creatorcontrib>Watanabe, Akira</creatorcontrib><creatorcontrib>Nonaka, Aya</creatorcontrib><creatorcontrib>Midorikawa, Yutaka</creatorcontrib><creatorcontrib>Makuuchi, Masatoshi</creatorcontrib><creatorcontrib>Shimamura, Takahiro</creatorcontrib><creatorcontrib>Sugimura, Haruhiko</creatorcontrib><creatorcontrib>Niida, Atsushi</creatorcontrib><creatorcontrib>Akiyama, Tetsu</creatorcontrib><creatorcontrib>Iwanari, Hiroko</creatorcontrib><creatorcontrib>Kodama, Tatsuhiko</creatorcontrib><creatorcontrib>Zeniya, Mikio</creatorcontrib><creatorcontrib>Aburatani, Hiroyuki</creatorcontrib><title>Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β‐catenin/TCF</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of β‐catenin protein: all 10 HCC with high intracellular β‐catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular β‐catenin had high NOTUM expression (P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant‐negative mutant of TCF4, a β‐catenin partner. In vivo binding of the β‐catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of β‐catenin/TCF4 and is upregulated in Wnt/β‐catenin signaling‐activated HCC. (Cancer Sci 2008; 99: 1139–1146)</description><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Antibodies, Monoclonal</subject><subject>beta Catenin - metabolism</subject><subject>Biological and medical sciences</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Chromatin Immunoprecipitation</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - immunology</subject><subject>Drosophila Proteins - metabolism</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunization</subject><subject>Immunoblotting</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Mutagenesis, Site-Directed</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Original /Report</subject><subject>Promoter Regions, Genetic</subject><subject>Rabbits</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - immunology</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>TCF Transcription Factors - genetics</subject><subject>TCF Transcription Factors - metabolism</subject><subject>Transcription Factor 7-Like 2 Protein</subject><subject>Transcription, Genetic</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>1347-9032</issn><issn>1349-7006</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkdFuFCEUhonR2Lr6CoYbvepOgWEGSExMs7HWpNoLt9eEZWDLhhlGmKm7dz6Cz-KD-BA-iUx3s-qdJIQTzncOh_8HAGJU4LzONwUuqZgzhOqCIMSLvDEtto_A6THx-CFmc4FKcgKepbRBqKypoE_BCeaUCFGRUzBeja3q4F1ogw9rGCz8dLO8_XgGw72JZttHk5JpoMuI6dUQtPF-9CpCraJ2XWjVGXQJRrPOt0Mmh6i6pKPrBxc65f0Ornbw549f377rnO9cd75cXD4HT6zyybw4nDNwe_luubiaX9-8_7C4uJ7rqqpo_gZjzFpR0obXosFUGcqF5ooou2Jl02jKrbC2Jvn3zJKaNyutSF0h2pCGiHIG3u779uOqNY02XR7Pyz66VsWdDMrJfzOdu5PrcC-zyBUXWbAZeH3oEMOX0aRBti5NIqjOhDHJPCLFtCIZ5HtQx5BSNPb4CkZTOyw3cvJGTt7IyTT5YJrc5tKXf0_5p_DgUgZeHQCVtPI2S6xdOnIElVwQxjL3Zs99dd7s_nsAubj4nIPyN2PLtrI</recordid><startdate>200806</startdate><enddate>200806</enddate><creator>Torisu, Yuichi</creator><creator>Watanabe, Akira</creator><creator>Nonaka, Aya</creator><creator>Midorikawa, Yutaka</creator><creator>Makuuchi, Masatoshi</creator><creator>Shimamura, Takahiro</creator><creator>Sugimura, Haruhiko</creator><creator>Niida, Atsushi</creator><creator>Akiyama, Tetsu</creator><creator>Iwanari, Hiroko</creator><creator>Kodama, Tatsuhiko</creator><creator>Zeniya, Mikio</creator><creator>Aburatani, Hiroyuki</creator><general>Blackwell Publishing Asia</general><general>Blackwell</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>200806</creationdate><title>Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β‐catenin/TCF</title><author>Torisu, Yuichi ; Watanabe, Akira ; Nonaka, Aya ; Midorikawa, Yutaka ; Makuuchi, Masatoshi ; Shimamura, Takahiro ; Sugimura, Haruhiko ; Niida, Atsushi ; Akiyama, Tetsu ; Iwanari, Hiroko ; Kodama, Tatsuhiko ; Zeniya, Mikio ; Aburatani, Hiroyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5554-70777ff934d869d14ae489c8a2afb73ddc48f9ff628147f268dbca26504d2d293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Antibodies, Monoclonal</topic><topic>beta Catenin - metabolism</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Chromatin Immunoprecipitation</topic><topic>Drosophila Proteins - genetics</topic><topic>Drosophila Proteins - immunology</topic><topic>Drosophila Proteins - metabolism</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunization</topic><topic>Immunoblotting</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Mutagenesis, Site-Directed</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Original /Report</topic><topic>Promoter Regions, Genetic</topic><topic>Rabbits</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Recombinant Fusion Proteins - immunology</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>TCF Transcription Factors - genetics</topic><topic>TCF Transcription Factors - metabolism</topic><topic>Transcription Factor 7-Like 2 Protein</topic><topic>Transcription, Genetic</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Torisu, Yuichi</creatorcontrib><creatorcontrib>Watanabe, Akira</creatorcontrib><creatorcontrib>Nonaka, Aya</creatorcontrib><creatorcontrib>Midorikawa, Yutaka</creatorcontrib><creatorcontrib>Makuuchi, Masatoshi</creatorcontrib><creatorcontrib>Shimamura, Takahiro</creatorcontrib><creatorcontrib>Sugimura, Haruhiko</creatorcontrib><creatorcontrib>Niida, Atsushi</creatorcontrib><creatorcontrib>Akiyama, Tetsu</creatorcontrib><creatorcontrib>Iwanari, Hiroko</creatorcontrib><creatorcontrib>Kodama, Tatsuhiko</creatorcontrib><creatorcontrib>Zeniya, Mikio</creatorcontrib><creatorcontrib>Aburatani, Hiroyuki</creatorcontrib><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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Torisu, Yuichi</au><au>Watanabe, Akira</au><au>Nonaka, Aya</au><au>Midorikawa, Yutaka</au><au>Makuuchi, Masatoshi</au><au>Shimamura, Takahiro</au><au>Sugimura, Haruhiko</au><au>Niida, Atsushi</au><au>Akiyama, Tetsu</au><au>Iwanari, Hiroko</au><au>Kodama, Tatsuhiko</au><au>Zeniya, Mikio</au><au>Aburatani, Hiroyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β‐catenin/TCF</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2008-06</date><risdate>2008</risdate><volume>99</volume><issue>6</issue><spage>1139</spage><epage>1146</epage><pages>1139-1146</pages><issn>1347-9032</issn><issn>1349-7006</issn><eissn>1349-7006</eissn><abstract>The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of β‐catenin protein: all 10 HCC with high intracellular β‐catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular β‐catenin had high NOTUM expression (P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant‐negative mutant of TCF4, a β‐catenin partner. In vivo binding of the β‐catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of β‐catenin/TCF4 and is upregulated in Wnt/β‐catenin signaling‐activated HCC. (Cancer Sci 2008; 99: 1139–1146)</abstract><cop>Melbourne, Australia</cop><pub>Blackwell Publishing Asia</pub><pmid>18429952</pmid><doi>10.1111/j.1349-7006.2008.00814.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Animals Antibodies, Monoclonal beta Catenin - metabolism Biological and medical sciences Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Chromatin Immunoprecipitation Drosophila Proteins - genetics Drosophila Proteins - immunology Drosophila Proteins - metabolism Female Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Immunization Immunoblotting Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Mice Middle Aged Mutagenesis, Site-Directed Oligonucleotide Array Sequence Analysis Original /Report Promoter Regions, Genetic Rabbits Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - immunology Recombinant Fusion Proteins - metabolism Signal Transduction TCF Transcription Factors - genetics TCF Transcription Factors - metabolism Transcription Factor 7-Like 2 Protein Transcription, Genetic Tumor Cells, Cultured Tumors |
| title | Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β‐catenin/TCF |
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