Epigenetic changes in Basal Cell Carcinoma affect SHH and WNT signaling components
The genetic background of Basal Cell Carcinoma (BCC) has been studied extensively, while its epigenetic makeup has received comparatively little attention. Epigenetic alterations such as promoter hypermethylation silence tumor suppressor genes (TSG) in several malignancies. We sought to analyze the...
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| Veröffentlicht in: | PloS one 2012-12, Vol.7 (12), p.e51710-e51710 |
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| creator | Brinkhuizen, Tjinta van den Hurk, Karin Winnepenninckx, Véronique J L de Hoon, Joep P van Marion, Ariënne M Veeck, Jürgen van Engeland, Manon van Steensel, Maurice A M |
| description | The genetic background of Basal Cell Carcinoma (BCC) has been studied extensively, while its epigenetic makeup has received comparatively little attention. Epigenetic alterations such as promoter hypermethylation silence tumor suppressor genes (TSG) in several malignancies.
We sought to analyze the promoter methylation status of ten putative (tumor suppressor) genes that are associated with Sonic Hedgehog (SHH), WNT signaling and (hair follicle) tumors in a large series of 112 BCC and 124 healthy control samples by methylation-specific PCR.
Gene promoters of SHH (P = 0.016), adenomatous polyposis coli (APC) (P = 0.003), secreted frizzled-related protein 5 (SFRP5) (P = 0.004) and Ras association domain family 1A (RASSF1A) (P = 0.023) showed significantly more methylation in BCC versus normal skin. mRNA levels of these four genes were reduced for APC and SFRP5 in BCC (n = 6) vs normal skin (n = 6). Down regulation of SHH, APC and RASSF1A could be confirmed on protein level as well (P |
| doi_str_mv | 10.1371/journal.pone.0051710 |
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We sought to analyze the promoter methylation status of ten putative (tumor suppressor) genes that are associated with Sonic Hedgehog (SHH), WNT signaling and (hair follicle) tumors in a large series of 112 BCC and 124 healthy control samples by methylation-specific PCR.
Gene promoters of SHH (P = 0.016), adenomatous polyposis coli (APC) (P = 0.003), secreted frizzled-related protein 5 (SFRP5) (P = 0.004) and Ras association domain family 1A (RASSF1A) (P = 0.023) showed significantly more methylation in BCC versus normal skin. mRNA levels of these four genes were reduced for APC and SFRP5 in BCC (n = 6) vs normal skin (n = 6). Down regulation of SHH, APC and RASSF1A could be confirmed on protein level as well (P<0.001 for all genes) by immunohistochemical staining. Increased canonical WNT activity was visualized by β-catenin staining, showing nuclear β-catenin in only 28/101 (27.7%) of BCC. Absence of nuclear β-catenin in some samples may be due to high levels of membranous E-cadherin (in 94.1% of the samples).
We provide evidence that promoter hypermethylation of key players within the SHH and WNT pathways is frequent in BCC, consistent with their known constitutive activation in BCC. Epigenetic gene silencing putatively contributes to BCC tumorigenesis, indicating new venues for treatment.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0051710</identifier><identifier>PMID: 23284750</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenomatous polyposis coli ; Aged ; Analysis ; Basal cell carcinoma ; Biology ; Breast cancer ; Carcinoma, Basal Cell - genetics ; Case-Control Studies ; Colorectal cancer ; Deoxyribonucleic acid ; Dermatology ; Developmental biology ; DNA ; DNA Methylation ; E-cadherin ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Female ; Frizzled protein ; Frizzled-related protein ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene silencing ; Genes ; Genetic aspects ; Genetic engineering ; Hedgehog protein ; Hedgehog Proteins - genetics ; Humans ; Immunohistochemistry ; Internal medicine ; Male ; Medicine ; Methylation ; mRNA ; Mutation ; Oncology ; Pathogenesis ; Pathology ; Polyposis coli ; Promoter Regions, Genetic - genetics ; RNA ; Signaling ; Silence ; Skin ; Skin - metabolism ; Skin cancer ; Skin Neoplasms - genetics ; Staining ; Tumor Cells, Cultured ; Tumor suppressor genes ; Tumor Suppressor Proteins - genetics ; Tumorigenesis ; Tumors ; Wnt protein ; Wnt Proteins - genetics ; β-Catenin</subject><ispartof>PloS one, 2012-12, Vol.7 (12), p.e51710-e51710</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Brinkhuizen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Brinkhuizen et al 2012 Brinkhuizen et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-c903af6f6577be870a45bea5eaae24a077651832024b44fc8464008053bfe5553</citedby><cites>FETCH-LOGICAL-c692t-c903af6f6577be870a45bea5eaae24a077651832024b44fc8464008053bfe5553</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/PMC3524166/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524166/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23284750$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Castresana, Javier S.</contributor><creatorcontrib>Brinkhuizen, Tjinta</creatorcontrib><creatorcontrib>van den Hurk, Karin</creatorcontrib><creatorcontrib>Winnepenninckx, Véronique J L</creatorcontrib><creatorcontrib>de Hoon, Joep P</creatorcontrib><creatorcontrib>van Marion, Ariënne M</creatorcontrib><creatorcontrib>Veeck, Jürgen</creatorcontrib><creatorcontrib>van Engeland, Manon</creatorcontrib><creatorcontrib>van Steensel, Maurice A M</creatorcontrib><title>Epigenetic changes in Basal Cell Carcinoma affect SHH and WNT signaling components</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The genetic background of Basal Cell Carcinoma (BCC) has been studied extensively, while its epigenetic makeup has received comparatively little attention. Epigenetic alterations such as promoter hypermethylation silence tumor suppressor genes (TSG) in several malignancies.
We sought to analyze the promoter methylation status of ten putative (tumor suppressor) genes that are associated with Sonic Hedgehog (SHH), WNT signaling and (hair follicle) tumors in a large series of 112 BCC and 124 healthy control samples by methylation-specific PCR.
Gene promoters of SHH (P = 0.016), adenomatous polyposis coli (APC) (P = 0.003), secreted frizzled-related protein 5 (SFRP5) (P = 0.004) and Ras association domain family 1A (RASSF1A) (P = 0.023) showed significantly more methylation in BCC versus normal skin. mRNA levels of these four genes were reduced for APC and SFRP5 in BCC (n = 6) vs normal skin (n = 6). Down regulation of SHH, APC and RASSF1A could be confirmed on protein level as well (P<0.001 for all genes) by immunohistochemical staining. Increased canonical WNT activity was visualized by β-catenin staining, showing nuclear β-catenin in only 28/101 (27.7%) of BCC. Absence of nuclear β-catenin in some samples may be due to high levels of membranous E-cadherin (in 94.1% of the samples).
We provide evidence that promoter hypermethylation of key players within the SHH and WNT pathways is frequent in BCC, consistent with their known constitutive activation in BCC. Epigenetic gene silencing putatively contributes to BCC tumorigenesis, indicating new venues for treatment.</description><subject>Adenomatous polyposis coli</subject><subject>Aged</subject><subject>Analysis</subject><subject>Basal cell carcinoma</subject><subject>Biology</subject><subject>Breast cancer</subject><subject>Carcinoma, Basal Cell - genetics</subject><subject>Case-Control Studies</subject><subject>Colorectal cancer</subject><subject>Deoxyribonucleic acid</subject><subject>Dermatology</subject><subject>Developmental biology</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>E-cadherin</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Frizzled protein</subject><subject>Frizzled-related protein</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene silencing</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic engineering</subject><subject>Hedgehog protein</subject><subject>Hedgehog Proteins - genetics</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Internal medicine</subject><subject>Male</subject><subject>Medicine</subject><subject>Methylation</subject><subject>mRNA</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Pathogenesis</subject><subject>Pathology</subject><subject>Polyposis coli</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>RNA</subject><subject>Signaling</subject><subject>Silence</subject><subject>Skin</subject><subject>Skin - metabolism</subject><subject>Skin cancer</subject><subject>Skin Neoplasms - genetics</subject><subject>Staining</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>Wnt Proteins - genetics</subject><subject>β-Catenin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1v0zAUhiMEYmPwDxBEQkJw0eJvOzdIoxq00sSkbcCldeo4qafE7uIEwb_HpdnUoF2gSI5lP-c95z0-WfYSozmmEn-4CUPnoZlvg7dzhDiWGD3KjnFByUwQRB8f7I-yZzHeJIgqIZ5mR4QSxSRHx9nl2dbV1tvemdxswNc25s7nnyBCky9skxbojPOhhRyqypo-v1ouc_Bl_uPrdR5dnWpwvs5NaHeV-D4-z55U0ET7YvyfZN8-n10vlrPziy-rxen5zIiC9DNTIAqVqASXcm2VRMD42gK3AJYwQFIKjhUliLA1Y5VRTDCEVPKwriznnJ5kr_e62yZEPbYjakyJxEoVrEjEak-UAW70tnMtdL91AKf_HoSu1tAl543VJrWGE2IKjhmzlgEtlZJYpNwKmbJMWh_HbMO6taVJTjtoJqLTG-82ug4_NeWEYSGSwLtRoAu3g429bl00qcPgbRhS3URSLLigO_TNP-jD7kaqhmTA-SqkvGYnqk-ZlEhyhWmi5g9Q6Stt60x6scql80nA-0lAYnr7q69hiFGvri7_n734PmXfHrAbC02_iaEZehd8nIJsD5ouxNjZ6r7JGOnd6N91Q-8GTo-jn8JeHT7QfdDdrNM_K3j7eA</recordid><startdate>20121217</startdate><enddate>20121217</enddate><creator>Brinkhuizen, Tjinta</creator><creator>van den Hurk, Karin</creator><creator>Winnepenninckx, Véronique J L</creator><creator>de Hoon, Joep P</creator><creator>van Marion, Ariënne M</creator><creator>Veeck, Jürgen</creator><creator>van Engeland, Manon</creator><creator>van Steensel, Maurice A M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20121217</creationdate><title>Epigenetic changes in Basal Cell Carcinoma affect SHH and WNT signaling components</title><author>Brinkhuizen, Tjinta ; van den Hurk, Karin ; Winnepenninckx, Véronique J L ; de Hoon, Joep P ; van Marion, Ariënne M ; Veeck, Jürgen ; van Engeland, Manon ; van Steensel, Maurice A M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-c903af6f6577be870a45bea5eaae24a077651832024b44fc8464008053bfe5553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenomatous polyposis coli</topic><topic>Aged</topic><topic>Analysis</topic><topic>Basal cell carcinoma</topic><topic>Biology</topic><topic>Breast cancer</topic><topic>Carcinoma, Basal Cell - genetics</topic><topic>Case-Control Studies</topic><topic>Colorectal cancer</topic><topic>Deoxyribonucleic acid</topic><topic>Dermatology</topic><topic>Developmental biology</topic><topic>DNA</topic><topic>DNA Methylation</topic><topic>E-cadherin</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>Epigenetics</topic><topic>Female</topic><topic>Frizzled protein</topic><topic>Frizzled-related protein</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene silencing</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic engineering</topic><topic>Hedgehog protein</topic><topic>Hedgehog Proteins - genetics</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Internal medicine</topic><topic>Male</topic><topic>Medicine</topic><topic>Methylation</topic><topic>mRNA</topic><topic>Mutation</topic><topic>Oncology</topic><topic>Pathogenesis</topic><topic>Pathology</topic><topic>Polyposis coli</topic><topic>Promoter Regions, Genetic - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brinkhuizen, Tjinta</au><au>van den Hurk, Karin</au><au>Winnepenninckx, Véronique J L</au><au>de Hoon, Joep P</au><au>van Marion, Ariënne M</au><au>Veeck, Jürgen</au><au>van Engeland, Manon</au><au>van Steensel, Maurice A M</au><au>Castresana, Javier S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epigenetic changes in Basal Cell Carcinoma affect SHH and WNT signaling components</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-12-17</date><risdate>2012</risdate><volume>7</volume><issue>12</issue><spage>e51710</spage><epage>e51710</epage><pages>e51710-e51710</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The genetic background of Basal Cell Carcinoma (BCC) has been studied extensively, while its epigenetic makeup has received comparatively little attention. Epigenetic alterations such as promoter hypermethylation silence tumor suppressor genes (TSG) in several malignancies.
We sought to analyze the promoter methylation status of ten putative (tumor suppressor) genes that are associated with Sonic Hedgehog (SHH), WNT signaling and (hair follicle) tumors in a large series of 112 BCC and 124 healthy control samples by methylation-specific PCR.
Gene promoters of SHH (P = 0.016), adenomatous polyposis coli (APC) (P = 0.003), secreted frizzled-related protein 5 (SFRP5) (P = 0.004) and Ras association domain family 1A (RASSF1A) (P = 0.023) showed significantly more methylation in BCC versus normal skin. mRNA levels of these four genes were reduced for APC and SFRP5 in BCC (n = 6) vs normal skin (n = 6). Down regulation of SHH, APC and RASSF1A could be confirmed on protein level as well (P<0.001 for all genes) by immunohistochemical staining. Increased canonical WNT activity was visualized by β-catenin staining, showing nuclear β-catenin in only 28/101 (27.7%) of BCC. Absence of nuclear β-catenin in some samples may be due to high levels of membranous E-cadherin (in 94.1% of the samples).
We provide evidence that promoter hypermethylation of key players within the SHH and WNT pathways is frequent in BCC, consistent with their known constitutive activation in BCC. Epigenetic gene silencing putatively contributes to BCC tumorigenesis, indicating new venues for treatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23284750</pmid><doi>10.1371/journal.pone.0051710</doi><tpages>e51710</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1327188949 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenomatous polyposis coli Aged Analysis Basal cell carcinoma Biology Breast cancer Carcinoma, Basal Cell - genetics Case-Control Studies Colorectal cancer Deoxyribonucleic acid Dermatology Developmental biology DNA DNA Methylation E-cadherin Epigenesis, Genetic Epigenetic inheritance Epigenetics Female Frizzled protein Frizzled-related protein Gene expression Gene Expression Regulation, Neoplastic Gene silencing Genes Genetic aspects Genetic engineering Hedgehog protein Hedgehog Proteins - genetics Humans Immunohistochemistry Internal medicine Male Medicine Methylation mRNA Mutation Oncology Pathogenesis Pathology Polyposis coli Promoter Regions, Genetic - genetics RNA Signaling Silence Skin Skin - metabolism Skin cancer Skin Neoplasms - genetics Staining Tumor Cells, Cultured Tumor suppressor genes Tumor Suppressor Proteins - genetics Tumorigenesis Tumors Wnt protein Wnt Proteins - genetics β-Catenin |
| title | Epigenetic changes in Basal Cell Carcinoma affect SHH and WNT signaling components |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T23%3A21%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Epigenetic%20changes%20in%20Basal%20Cell%20Carcinoma%20affect%20SHH%20and%20WNT%20signaling%20components&rft.jtitle=PloS%20one&rft.au=Brinkhuizen,%20Tjinta&rft.date=2012-12-17&rft.volume=7&rft.issue=12&rft.spage=e51710&rft.epage=e51710&rft.pages=e51710-e51710&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0051710&rft_dat=%3Cgale_plos_%3EA477075813%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1327188949&rft_id=info:pmid/23284750&rft_galeid=A477075813&rft_doaj_id=oai_doaj_org_article_c538522c95144ee4a3d887164b480cdd&rfr_iscdi=true |