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Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors
The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four s...
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| Published in: | Endocrinology (Philadelphia) 2008-03, Vol.149 (3), p.1235-1242 |
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| creator | Elston, Marianne S Gill, Anthony J Conaglen, John V Clarkson, Adele Shaw, Janet M Law, Andrew J. J Cook, Raymond J Little, Nicholas S Clifton-Bligh, Roderick J Robinson, Bruce G McDonald, Kerrie L |
| description | The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four secreted frizzled-related protein (sFRP) family members of Wnt pathway inhibitors that were differentially expressed in both nonfunctioning and clinically functioning pituitary tumors (n = 20) compared with normal pituitary controls (n = 3). Reduced tumor expression of Wnt inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed by real-time quantitative RT-PCR (P |
| doi_str_mv | 10.1210/en.2007-0542 |
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J ; Cook, Raymond J ; Little, Nicholas S ; Clifton-Bligh, Roderick J ; Robinson, Bruce G ; McDonald, Kerrie L</creator><creatorcontrib>Elston, Marianne S ; Gill, Anthony J ; Conaglen, John V ; Clarkson, Adele ; Shaw, Janet M ; Law, Andrew J. J ; Cook, Raymond J ; Little, Nicholas S ; Clifton-Bligh, Roderick J ; Robinson, Bruce G ; McDonald, Kerrie L</creatorcontrib><description>The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four secreted frizzled-related protein (sFRP) family members of Wnt pathway inhibitors that were differentially expressed in both nonfunctioning and clinically functioning pituitary tumors (n = 20) compared with normal pituitary controls (n = 3). Reduced tumor expression of Wnt inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed by real-time quantitative RT-PCR (P <0.001 and P = 0.002 and 0.013, respectively) in all pituitary subtypes. Hypermethylation of the WIF1 promoter was present in 88% of the pituitary tumors (n = 41). Seventy-six percent of pituitary tumors demonstrated absent or weak cytoplasmic WIF1 staining by immunohistochemistry (n = 41), although preserved staining was seen in some functioning tumors, with strong staining in 92% of normal pituitary controls (n = 13). The Wnt pathway target gene cyclin D1 was found to be up-regulated specifically in the nonfunctioning pituitary tumors compared with controls at both mRNA and protein level, supportive of activation of the Wnt-β-catenin pathway. Nuclear accumulation of β-catenin, however, was not observed in any pituitary tumors (n = 70). By transfecting GH3 cells with WIF1, decreased cell proliferation and colony formation was observed compared with empty vector controls. In conclusion, our data suggest that WIF1 may be a tumor suppressor, specifically in nonfunctioning pituitary tumors, and that the Wnt pathways are important in pituitary tumorigenesis.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2007-0542</identifier><identifier>PMID: 18079202</identifier><identifier>CODEN: ENDOAO</identifier><language>eng</language><publisher>Bethesda, MD: Endocrine Society</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Adult ; Aged ; Aged, 80 and over ; Animals ; beta Catenin - metabolism ; Biological and medical sciences ; Brain tumors ; Case-Control Studies ; Cell Line ; Cell Proliferation ; Cyclin D1 ; Cyclin D1 - metabolism ; DNA microarrays ; Down-Regulation - physiology ; Extracellular Matrix Proteins - metabolism ; Female ; Frizzled protein ; Frizzled-related protein ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene Expression Regulation, Neoplastic - physiology ; Glycoproteins - metabolism ; Humans ; Immunohistochemistry ; Inhibitors ; Intercellular Signaling Peptides and Proteins - metabolism ; Male ; Membrane Proteins - metabolism ; Middle Aged ; mRNA ; Pathogenesis ; Pituitary ; Pituitary Neoplasms - etiology ; Pituitary Neoplasms - metabolism ; Pituitary Neoplasms - pathology ; Protein arrays ; Proteins ; Proto-Oncogene Proteins - metabolism ; Rats ; Real time ; Repressor Proteins - metabolism ; Somatotrophs - metabolism ; Staining ; Transfection ; Tumor suppressor genes ; Tumorigenesis ; Tumors ; Vertebrates: endocrinology ; Wnt protein ; β-Catenin</subject><ispartof>Endocrinology (Philadelphia), 2008-03, Vol.149 (3), p.1235-1242</ispartof><rights>Copyright © 2008 by the Endocrine Society 2008</rights><rights>2008 INIST-CNRS</rights><rights>Copyright © 2008 by the Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c558t-8c2508d617cdf66e3ee3a649ac962269bd5419da7ec021005684ca5f67c12c053</citedby><cites>FETCH-LOGICAL-c558t-8c2508d617cdf66e3ee3a649ac962269bd5419da7ec021005684ca5f67c12c053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20318167$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18079202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Elston, Marianne S</creatorcontrib><creatorcontrib>Gill, Anthony J</creatorcontrib><creatorcontrib>Conaglen, John V</creatorcontrib><creatorcontrib>Clarkson, Adele</creatorcontrib><creatorcontrib>Shaw, Janet M</creatorcontrib><creatorcontrib>Law, Andrew J. J</creatorcontrib><creatorcontrib>Cook, Raymond J</creatorcontrib><creatorcontrib>Little, Nicholas S</creatorcontrib><creatorcontrib>Clifton-Bligh, Roderick J</creatorcontrib><creatorcontrib>Robinson, Bruce G</creatorcontrib><creatorcontrib>McDonald, Kerrie L</creatorcontrib><title>Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four secreted frizzled-related protein (sFRP) family members of Wnt pathway inhibitors that were differentially expressed in both nonfunctioning and clinically functioning pituitary tumors (n = 20) compared with normal pituitary controls (n = 3). Reduced tumor expression of Wnt inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed by real-time quantitative RT-PCR (P <0.001 and P = 0.002 and 0.013, respectively) in all pituitary subtypes. Hypermethylation of the WIF1 promoter was present in 88% of the pituitary tumors (n = 41). Seventy-six percent of pituitary tumors demonstrated absent or weak cytoplasmic WIF1 staining by immunohistochemistry (n = 41), although preserved staining was seen in some functioning tumors, with strong staining in 92% of normal pituitary controls (n = 13). The Wnt pathway target gene cyclin D1 was found to be up-regulated specifically in the nonfunctioning pituitary tumors compared with controls at both mRNA and protein level, supportive of activation of the Wnt-β-catenin pathway. Nuclear accumulation of β-catenin, however, was not observed in any pituitary tumors (n = 70). By transfecting GH3 cells with WIF1, decreased cell proliferation and colony formation was observed compared with empty vector controls. In conclusion, our data suggest that WIF1 may be a tumor suppressor, specifically in nonfunctioning pituitary tumors, and that the Wnt pathways are important in pituitary tumorigenesis.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Animals</subject><subject>beta Catenin - metabolism</subject><subject>Biological and medical sciences</subject><subject>Brain tumors</subject><subject>Case-Control Studies</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Cyclin D1</subject><subject>Cyclin D1 - metabolism</subject><subject>DNA microarrays</subject><subject>Down-Regulation - physiology</subject><subject>Extracellular Matrix Proteins - metabolism</subject><subject>Female</subject><subject>Frizzled protein</subject><subject>Frizzled-related protein</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>Glycoproteins - metabolism</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inhibitors</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Male</subject><subject>Membrane Proteins - metabolism</subject><subject>Middle Aged</subject><subject>mRNA</subject><subject>Pathogenesis</subject><subject>Pituitary</subject><subject>Pituitary Neoplasms - etiology</subject><subject>Pituitary Neoplasms - metabolism</subject><subject>Pituitary Neoplasms - pathology</subject><subject>Protein arrays</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Rats</subject><subject>Real time</subject><subject>Repressor Proteins - metabolism</subject><subject>Somatotrophs - metabolism</subject><subject>Staining</subject><subject>Transfection</subject><subject>Tumor suppressor genes</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Vertebrates: endocrinology</subject><subject>Wnt protein</subject><subject>β-Catenin</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNqF0d9rFDEQB_AgFntW33yWBVFfunXye_ex1NYWChat-Bhy2dl2y15yTbKU---b4xYLRfEpBD7MzHeGkHcUjiij8AX9EQPQNUjBXpAFbYWsNdXwkiwAKK81Y3qfvE7prnyFEPwV2acN6JYBW5Cz3z5XVzbfPthNdeFvh-WQQ0zVccTqZ47B34yb6mt48PUPvJlGm7GrBl9dDXkaso2b6npaFf-G7PV2TPh2fg_Ir7PT65Pz-vL7t4uT48vaSdnkunFMQtMpql3XK4UckVslWutaxZhql50UtO2sRgclG0jVCGdlr7SjzIHkB-TTru46hvsJUzarITkcR-sxTMlo4KxkZ_-FrNTmXOgCPzyDd2GKvoQwnHKQTauFKupwp1wMKUXszToOq5LfUDDbMxj0ZnsGsz1D4e_notNyhd0TnvdewMcZ2OTs2Efr3ZD-OAacNlRtp_u8c2Fa_6tlPbfkO4m-Cy4OHtcRU3pK89dBHwGqOqpU</recordid><startdate>20080301</startdate><enddate>20080301</enddate><creator>Elston, Marianne S</creator><creator>Gill, Anthony J</creator><creator>Conaglen, John V</creator><creator>Clarkson, Adele</creator><creator>Shaw, Janet M</creator><creator>Law, Andrew J. 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Psychology</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Glycoproteins - metabolism</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Inhibitors</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Male</topic><topic>Membrane Proteins - metabolism</topic><topic>Middle Aged</topic><topic>mRNA</topic><topic>Pathogenesis</topic><topic>Pituitary</topic><topic>Pituitary Neoplasms - etiology</topic><topic>Pituitary Neoplasms - metabolism</topic><topic>Pituitary Neoplasms - pathology</topic><topic>Protein arrays</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Rats</topic><topic>Real time</topic><topic>Repressor Proteins - metabolism</topic><topic>Somatotrophs - metabolism</topic><topic>Staining</topic><topic>Transfection</topic><topic>Tumor suppressor genes</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>Vertebrates: endocrinology</topic><topic>Wnt protein</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Elston, Marianne S</creatorcontrib><creatorcontrib>Gill, Anthony J</creatorcontrib><creatorcontrib>Conaglen, John V</creatorcontrib><creatorcontrib>Clarkson, Adele</creatorcontrib><creatorcontrib>Shaw, Janet M</creatorcontrib><creatorcontrib>Law, Andrew J. 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J</au><au>Cook, Raymond J</au><au>Little, Nicholas S</au><au>Clifton-Bligh, Roderick J</au><au>Robinson, Bruce G</au><au>McDonald, Kerrie L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2008-03-01</date><risdate>2008</risdate><volume>149</volume><issue>3</issue><spage>1235</spage><epage>1242</epage><pages>1235-1242</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><coden>ENDOAO</coden><abstract>The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four secreted frizzled-related protein (sFRP) family members of Wnt pathway inhibitors that were differentially expressed in both nonfunctioning and clinically functioning pituitary tumors (n = 20) compared with normal pituitary controls (n = 3). Reduced tumor expression of Wnt inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed by real-time quantitative RT-PCR (P <0.001 and P = 0.002 and 0.013, respectively) in all pituitary subtypes. Hypermethylation of the WIF1 promoter was present in 88% of the pituitary tumors (n = 41). Seventy-six percent of pituitary tumors demonstrated absent or weak cytoplasmic WIF1 staining by immunohistochemistry (n = 41), although preserved staining was seen in some functioning tumors, with strong staining in 92% of normal pituitary controls (n = 13). The Wnt pathway target gene cyclin D1 was found to be up-regulated specifically in the nonfunctioning pituitary tumors compared with controls at both mRNA and protein level, supportive of activation of the Wnt-β-catenin pathway. Nuclear accumulation of β-catenin, however, was not observed in any pituitary tumors (n = 70). By transfecting GH3 cells with WIF1, decreased cell proliferation and colony formation was observed compared with empty vector controls. In conclusion, our data suggest that WIF1 may be a tumor suppressor, specifically in nonfunctioning pituitary tumors, and that the Wnt pathways are important in pituitary tumorigenesis.</abstract><cop>Bethesda, MD</cop><pub>Endocrine Society</pub><pmid>18079202</pmid><doi>10.1210/en.2007-0542</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - metabolism Adult Aged Aged, 80 and over Animals beta Catenin - metabolism Biological and medical sciences Brain tumors Case-Control Studies Cell Line Cell Proliferation Cyclin D1 Cyclin D1 - metabolism DNA microarrays Down-Regulation - physiology Extracellular Matrix Proteins - metabolism Female Frizzled protein Frizzled-related protein Fundamental and applied biological sciences. Psychology Gene expression Gene Expression Regulation, Neoplastic - physiology Glycoproteins - metabolism Humans Immunohistochemistry Inhibitors Intercellular Signaling Peptides and Proteins - metabolism Male Membrane Proteins - metabolism Middle Aged mRNA Pathogenesis Pituitary Pituitary Neoplasms - etiology Pituitary Neoplasms - metabolism Pituitary Neoplasms - pathology Protein arrays Proteins Proto-Oncogene Proteins - metabolism Rats Real time Repressor Proteins - metabolism Somatotrophs - metabolism Staining Transfection Tumor suppressor genes Tumorigenesis Tumors Vertebrates: endocrinology Wnt protein β-Catenin |
| title | Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors |
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