DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines
Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible f...
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| Veröffentlicht in: | International journal of molecular sciences 2022-02, Vol.23 (4), p.2117 |
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| creator | Urbanova, Maria Buocikova, Verona Trnkova, Lenka Strapcova, Sabina Kajabova, Viera Horvathova Melian, Emma Barreto Novisedlakova, Maria Tomas, Miroslav Dubovan, Peter Earl, Julie Bizik, Jozef Svastova, Eliska Ciernikova, Sona Smolkova, Bozena |
| description | Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O
) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression. |
| doi_str_mv | 10.3390/ijms23042117 |
| format | Article |
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) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms23042117</identifier><identifier>PMID: 35216235</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>5-aza-2'-deoxycytidine ; Adenocarcinoma ; Biomarkers, Tumor - genetics ; Cancer ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - pathology ; Cell Line, Tumor ; Cell Movement - genetics ; Cell Proliferation - genetics ; Chemokines ; Crosstalk ; Cytokines ; Deoxyribonucleic acid ; Deregulation ; DNA ; DNA methylation ; DNA Methylation - genetics ; DNA methyltransferase ; EMT gene ; Enzymes ; Epigenesis, Genetic - genetics ; Epigenetics ; Epithelial-Mesenchymal Transition - genetics ; Extracellular matrix ; Gene expression ; Gene Expression - genetics ; Gene Expression Regulation, Neoplastic - genetics ; Gene regulation ; Gene silencing ; Genes ; Growth factors ; Humans ; Hypoxia ; Inflammation ; Ligands ; Medical prognosis ; Mesenchyme ; Metastasis ; Mutation ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Polymerase chain reaction ; Prognosis ; Stroma ; Tumor cell lines ; Tumors ; Vascularization</subject><ispartof>International journal of molecular sciences, 2022-02, Vol.23 (4), p.2117</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O
) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.</description><subject>5-aza-2'-deoxycytidine</subject><subject>Adenocarcinoma</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Cancer</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Cell Proliferation - genetics</subject><subject>Chemokines</subject><subject>Crosstalk</subject><subject>Cytokines</subject><subject>Deoxyribonucleic acid</subject><subject>Deregulation</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>DNA methyltransferase</subject><subject>EMT gene</subject><subject>Enzymes</subject><subject>Epigenesis, Genetic - genetics</subject><subject>Epigenetics</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Extracellular matrix</subject><subject>Gene expression</subject><subject>Gene Expression - genetics</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Gene regulation</subject><subject>Gene silencing</subject><subject>Genes</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Inflammation</subject><subject>Ligands</subject><subject>Medical prognosis</subject><subject>Mesenchyme</subject><subject>Metastasis</subject><subject>Mutation</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Polymerase chain reaction</subject><subject>Prognosis</subject><subject>Stroma</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Vascularization</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1LJDEQxYMoq6t78ywBLx6cNR-dTuciDOOsLoy6B_cc0ulqzdCdjEm36H9vBj8YPdWD-tWjHg-hQ0p-c67ImVv2iXFSMErlFtqjBWMTQkq5vaF30c-UloQwzoT6gXa5YLRkXOwhc3EzxdcwPLx0ZnDBZ904M0DC8-s7fAke8Px5FSGl9dJ5fDX2xuN_xtsI-cLii9EOpsPTBnywJlrnQ2_wDLoOL5yHdIB2WtMl-PU-99H_P_O72dVkcXv5dzZdTGxB2TBRtiorUwqgFW1Um1XNaskEkaRQomitZVS0tuCcEmXA2Bq4kHU-o62sG8v30fmb72qse2gs-CGaTq-i60180cE4_XXj3YO-D0-6qqQilcwGJ-8GMTyOkAbdu2RzDuMhjEmzkvNKKMJERo-_ocswRp_jrSkmS64UydTpG2VjSClC-_kMJXrdnd7sLuNHmwE-4Y-y-CuhiJUa</recordid><startdate>20220214</startdate><enddate>20220214</enddate><creator>Urbanova, Maria</creator><creator>Buocikova, Verona</creator><creator>Trnkova, Lenka</creator><creator>Strapcova, Sabina</creator><creator>Kajabova, Viera Horvathova</creator><creator>Melian, Emma Barreto</creator><creator>Novisedlakova, Maria</creator><creator>Tomas, Miroslav</creator><creator>Dubovan, Peter</creator><creator>Earl, Julie</creator><creator>Bizik, Jozef</creator><creator>Svastova, Eliska</creator><creator>Ciernikova, Sona</creator><creator>Smolkova, Bozena</creator><general>MDPI AG</general><general>MDPI</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1114-5120</orcidid><orcidid>https://orcid.org/0000-0003-3510-9914</orcidid><orcidid>https://orcid.org/0000-0001-9360-4716</orcidid><orcidid>https://orcid.org/0000-0003-0679-1061</orcidid><orcidid>https://orcid.org/0000-0002-0410-2261</orcidid><orcidid>https://orcid.org/0000-0002-2466-9126</orcidid><orcidid>https://orcid.org/0000-0002-7081-0602</orcidid><orcidid>https://orcid.org/0000-0002-4906-5652</orcidid><orcidid>https://orcid.org/0000-0002-0853-4045</orcidid><orcidid>https://orcid.org/0000-0002-8139-6945</orcidid><orcidid>https://orcid.org/0000-0003-0931-0032</orcidid></search><sort><creationdate>20220214</creationdate><title>DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines</title><author>Urbanova, Maria ; Buocikova, Verona ; Trnkova, Lenka ; Strapcova, Sabina ; Kajabova, Viera Horvathova ; Melian, Emma Barreto ; Novisedlakova, Maria ; Tomas, Miroslav ; Dubovan, Peter ; Earl, Julie ; Bizik, Jozef ; Svastova, Eliska ; Ciernikova, Sona ; Smolkova, Bozena</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-9c868a65e181d9fa65b2b7250704954fcc215fc433109aeacbe357b9c81f7bdc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>5-aza-2'-deoxycytidine</topic><topic>Adenocarcinoma</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Cancer</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - genetics</topic><topic>Cell Proliferation - genetics</topic><topic>Chemokines</topic><topic>Crosstalk</topic><topic>Cytokines</topic><topic>Deoxyribonucleic acid</topic><topic>Deregulation</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA Methylation - genetics</topic><topic>DNA methyltransferase</topic><topic>EMT gene</topic><topic>Enzymes</topic><topic>Epigenesis, Genetic - genetics</topic><topic>Epigenetics</topic><topic>Epithelial-Mesenchymal Transition - genetics</topic><topic>Extracellular matrix</topic><topic>Gene expression</topic><topic>Gene Expression - genetics</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Gene regulation</topic><topic>Gene silencing</topic><topic>Genes</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Inflammation</topic><topic>Ligands</topic><topic>Medical prognosis</topic><topic>Mesenchyme</topic><topic>Metastasis</topic><topic>Mutation</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms</topic><topic>Pancreatic Neoplasms - 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Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O
) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>35216235</pmid><doi>10.3390/ijms23042117</doi><orcidid>https://orcid.org/0000-0002-1114-5120</orcidid><orcidid>https://orcid.org/0000-0003-3510-9914</orcidid><orcidid>https://orcid.org/0000-0001-9360-4716</orcidid><orcidid>https://orcid.org/0000-0003-0679-1061</orcidid><orcidid>https://orcid.org/0000-0002-0410-2261</orcidid><orcidid>https://orcid.org/0000-0002-2466-9126</orcidid><orcidid>https://orcid.org/0000-0002-7081-0602</orcidid><orcidid>https://orcid.org/0000-0002-4906-5652</orcidid><orcidid>https://orcid.org/0000-0002-0853-4045</orcidid><orcidid>https://orcid.org/0000-0002-8139-6945</orcidid><orcidid>https://orcid.org/0000-0003-0931-0032</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1422-0067 |
| ispartof | International journal of molecular sciences, 2022-02, Vol.23 (4), p.2117 |
| issn | 1422-0067 1661-6596 1422-0067 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8879087 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | 5-aza-2'-deoxycytidine Adenocarcinoma Biomarkers, Tumor - genetics Cancer Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - pathology Cell Line, Tumor Cell Movement - genetics Cell Proliferation - genetics Chemokines Crosstalk Cytokines Deoxyribonucleic acid Deregulation DNA DNA methylation DNA Methylation - genetics DNA methyltransferase EMT gene Enzymes Epigenesis, Genetic - genetics Epigenetics Epithelial-Mesenchymal Transition - genetics Extracellular matrix Gene expression Gene Expression - genetics Gene Expression Regulation, Neoplastic - genetics Gene regulation Gene silencing Genes Growth factors Humans Hypoxia Inflammation Ligands Medical prognosis Mesenchyme Metastasis Mutation Pancreas Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Polymerase chain reaction Prognosis Stroma Tumor cell lines Tumors Vascularization |
| title | DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines |
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