5-Aza-2’-deoxycytidine induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment
Hypoxia is associated with tumor aggressiveness and poor prognosis, including breast cancer. Low oxygen levels induces global genomic hypomethylation and hypermethylation of specific loci in tumor cells. DNA methylation is a reversible epigenetic modification, usually associated with gene silencing,...
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| Veröffentlicht in: | Molecular biology reports 2021-02, Vol.48 (2), p.1161-1169 |
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| creator | Salviano Soares de Amorim, Ísis Rodrigues, Juliana Alves Nicolau, Pedro König, Sandra Panis, Carolina de Souza da Fonseca, Adenilson Mencalha, Andre Luiz |
| description | Hypoxia is associated with tumor aggressiveness and poor prognosis, including breast cancer. Low oxygen levels induces global genomic hypomethylation and hypermethylation of specific loci in tumor cells. DNA methylation is a reversible epigenetic modification, usually associated with gene silencing, contributing to carcinogenesis and tumor progression. Since the effects of DNA methyltransferase inhibitor are context-dependent and as there is little data comparing their molecular effects in normoxic and hypoxic microenvironments in breast cancer, this study aimed to understand the gene expression profiles and molecular effects in response to treatment with DNA methyltransferase inhibitor in normoxia and hypoxia, using the breast cancer model. For this, a cDNA microarray was used to analyze the changes in the transcriptome upon treatment with DNA methyltransferase inhibitor (5-Aza-2’-deoxycytidine: 5-Aza-2’-dC), in normoxia and hypoxia. Furthermore, immunocytochemistry was performed to investigate the effect of 5-Aza-2’-dC on NF-κB/p65 inflammation regulator subcellular localization and expression, in normoxia and hypoxia conditions. We observed that proinflammatory pathways were upregulated by treatment with 5-Aza-2’-dC, in both conditions. However, treatment with 5-Aza-2’-dC in normoxia showed a greater amount of overexpressed proinflammatory pathways than 5-Aza-2’-dC in hypoxia. In this sense, we observed that the NF-κB expression increased only upon 5-Aza-2’-dC in normoxia. Moreover, nuclear staining for NF-κB and NF-κB target genes upregulation,
IL1A
and
IL1B
, were also observed after 5-Aza-2’-dC in normoxia. Our results suggest that 5-Aza-2’-dC induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment. These data may support further studies and expand the understanding of the DNA methyltransferase inhibitor effects in different tumor contexts. |
| doi_str_mv | 10.1007/s11033-020-05931-4 |
| format | Article |
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IL1A
and
IL1B
, were also observed after 5-Aza-2’-dC in normoxia. Our results suggest that 5-Aza-2’-dC induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment. These data may support further studies and expand the understanding of the DNA methyltransferase inhibitor effects in different tumor contexts.</description><identifier>ISSN: 0301-4851</identifier><identifier>EISSN: 1573-4978</identifier><identifier>DOI: 10.1007/s11033-020-05931-4</identifier><identifier>PMID: 33547534</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Acetylation - drug effects ; Animal Anatomy ; Animal Biochemistry ; Biomedical and Life Sciences ; Breast cancer ; Carcinogenesis ; Cell Line, Tumor ; Decitabine - pharmacology ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - drug effects ; DNA methyltransferase ; DNA microarrays ; DNA Modification Methylases - antagonists & inhibitors ; DNA Modification Methylases - genetics ; Enzyme Inhibitors - pharmacology ; Epigenesis, Genetic - genetics ; Epigenetics ; Gene expression ; Gene silencing ; Histology ; Humans ; Hypoxia ; IL-1β ; Immunocytochemistry ; Inflammation ; Inflammation - chemically induced ; Inflammation - genetics ; Inflammation - pathology ; Interleukin 1 ; Life Sciences ; Localization ; Morphology ; NF-κB protein ; Original Article ; Promoter Regions, Genetic - drug effects ; Promoter Regions, Genetic - genetics ; Transcription Factor RelA - genetics ; Transcriptomes ; Tumor cells ; Tumor Hypoxia - drug effects ; Tumor microenvironment ; Tumor Microenvironment - drug effects ; Tumor Microenvironment - genetics</subject><ispartof>Molecular biology reports, 2021-02, Vol.48 (2), p.1161-1169</ispartof><rights>Springer Nature B.V. 2021</rights><rights>Springer Nature B.V. 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-3df904e930085e21c3fb1e14f19c3b1dd6f2b7d78b5929352892290db679a3623</citedby><cites>FETCH-LOGICAL-c375t-3df904e930085e21c3fb1e14f19c3b1dd6f2b7d78b5929352892290db679a3623</cites><orcidid>0000-0002-4139-4080 ; 0000-0002-2762-1400 ; 0000-0002-0104-4369 ; 0000-0003-3322-2120 ; 0000-0002-4441-4008 ; 0000-0002-9400-076X ; 0000-0003-3229-8094</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11033-020-05931-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11033-020-05931-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33547534$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Salviano Soares de Amorim, Ísis</creatorcontrib><creatorcontrib>Rodrigues, Juliana Alves</creatorcontrib><creatorcontrib>Nicolau, Pedro</creatorcontrib><creatorcontrib>König, Sandra</creatorcontrib><creatorcontrib>Panis, Carolina</creatorcontrib><creatorcontrib>de Souza da Fonseca, Adenilson</creatorcontrib><creatorcontrib>Mencalha, Andre Luiz</creatorcontrib><title>5-Aza-2’-deoxycytidine induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment</title><title>Molecular biology reports</title><addtitle>Mol Biol Rep</addtitle><addtitle>Mol Biol Rep</addtitle><description>Hypoxia is associated with tumor aggressiveness and poor prognosis, including breast cancer. Low oxygen levels induces global genomic hypomethylation and hypermethylation of specific loci in tumor cells. DNA methylation is a reversible epigenetic modification, usually associated with gene silencing, contributing to carcinogenesis and tumor progression. Since the effects of DNA methyltransferase inhibitor are context-dependent and as there is little data comparing their molecular effects in normoxic and hypoxic microenvironments in breast cancer, this study aimed to understand the gene expression profiles and molecular effects in response to treatment with DNA methyltransferase inhibitor in normoxia and hypoxia, using the breast cancer model. For this, a cDNA microarray was used to analyze the changes in the transcriptome upon treatment with DNA methyltransferase inhibitor (5-Aza-2’-deoxycytidine: 5-Aza-2’-dC), in normoxia and hypoxia. Furthermore, immunocytochemistry was performed to investigate the effect of 5-Aza-2’-dC on NF-κB/p65 inflammation regulator subcellular localization and expression, in normoxia and hypoxia conditions. We observed that proinflammatory pathways were upregulated by treatment with 5-Aza-2’-dC, in both conditions. However, treatment with 5-Aza-2’-dC in normoxia showed a greater amount of overexpressed proinflammatory pathways than 5-Aza-2’-dC in hypoxia. In this sense, we observed that the NF-κB expression increased only upon 5-Aza-2’-dC in normoxia. Moreover, nuclear staining for NF-κB and NF-κB target genes upregulation,
IL1A
and
IL1B
, were also observed after 5-Aza-2’-dC in normoxia. Our results suggest that 5-Aza-2’-dC induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment. These data may support further studies and expand the understanding of the DNA methyltransferase inhibitor effects in different tumor contexts.</description><subject>Acetylation - drug effects</subject><subject>Animal Anatomy</subject><subject>Animal Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Breast cancer</subject><subject>Carcinogenesis</subject><subject>Cell Line, Tumor</subject><subject>Decitabine - pharmacology</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - drug effects</subject><subject>DNA methyltransferase</subject><subject>DNA microarrays</subject><subject>DNA Modification Methylases - antagonists & inhibitors</subject><subject>DNA Modification Methylases - genetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epigenesis, Genetic - genetics</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Gene silencing</subject><subject>Histology</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>IL-1β</subject><subject>Immunocytochemistry</subject><subject>Inflammation</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - genetics</subject><subject>Inflammation - pathology</subject><subject>Interleukin 1</subject><subject>Life Sciences</subject><subject>Localization</subject><subject>Morphology</subject><subject>NF-κB protein</subject><subject>Original Article</subject><subject>Promoter Regions, Genetic - drug effects</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Transcription Factor RelA - genetics</subject><subject>Transcriptomes</subject><subject>Tumor cells</subject><subject>Tumor Hypoxia - drug effects</subject><subject>Tumor microenvironment</subject><subject>Tumor Microenvironment - drug effects</subject><subject>Tumor Microenvironment - genetics</subject><issn>0301-4851</issn><issn>1573-4978</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kLtuFTEQhi0EIofAC1AgS7Qx-Hq8LqOImxSJBmrLa8_mbLS2D_ZulKWi5BV4PZ4Ehw3QUY1m_M0_1ofQc0ZfMUr168oYFYJQTglVRjAiH6AdU1oQaXT3EO2ooG3YKXaCntR6TSmVTKvH6EQIJbUScoe-K3L-1RH-89sPEiDfrn6dxzAmwGMKi4eKHb4q4GYobTJMLkY357Jif3DpCs6wm_F8ABzzBH6ZXMET3MBUzxqNUy4x346-ES7hw3rcmiXmguPoS4Z0M5acIqT5KXo0uKnCs_t6ij6_ffPp4j25_Pjuw8X5JfFCq5mIMBgqwQhKOwWceTH0DJgcmPGiZyHsB97roLteGW6E4p3h3NDQ77VxYs_FKXq55R5L_rJAne11XkpqJy1XWmupO3pH8Y1qn6y1wGCPZYyurJZReyffbvJtk29_y7eyLb24j176COHvyh_bDRAbUNtTs1f-3f5P7C8MrJGn</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Salviano Soares de Amorim, Ísis</creator><creator>Rodrigues, Juliana Alves</creator><creator>Nicolau, Pedro</creator><creator>König, Sandra</creator><creator>Panis, Carolina</creator><creator>de Souza da Fonseca, Adenilson</creator><creator>Mencalha, Andre Luiz</creator><general>Springer Netherlands</general><general>Springer Nature B.V</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>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0002-4139-4080</orcidid><orcidid>https://orcid.org/0000-0002-2762-1400</orcidid><orcidid>https://orcid.org/0000-0002-0104-4369</orcidid><orcidid>https://orcid.org/0000-0003-3322-2120</orcidid><orcidid>https://orcid.org/0000-0002-4441-4008</orcidid><orcidid>https://orcid.org/0000-0002-9400-076X</orcidid><orcidid>https://orcid.org/0000-0003-3229-8094</orcidid></search><sort><creationdate>20210201</creationdate><title>5-Aza-2’-deoxycytidine induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment</title><author>Salviano Soares de Amorim, Ísis ; Rodrigues, Juliana Alves ; Nicolau, Pedro ; König, Sandra ; Panis, Carolina ; de Souza da Fonseca, Adenilson ; Mencalha, Andre Luiz</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-3df904e930085e21c3fb1e14f19c3b1dd6f2b7d78b5929352892290db679a3623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acetylation - drug effects</topic><topic>Animal Anatomy</topic><topic>Animal Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Breast cancer</topic><topic>Carcinogenesis</topic><topic>Cell Line, Tumor</topic><topic>Decitabine - pharmacology</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA Methylation - drug effects</topic><topic>DNA methyltransferase</topic><topic>DNA microarrays</topic><topic>DNA Modification Methylases - antagonists & inhibitors</topic><topic>DNA Modification Methylases - genetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epigenesis, Genetic - genetics</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Gene silencing</topic><topic>Histology</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>IL-1β</topic><topic>Immunocytochemistry</topic><topic>Inflammation</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - genetics</topic><topic>Inflammation - pathology</topic><topic>Interleukin 1</topic><topic>Life Sciences</topic><topic>Localization</topic><topic>Morphology</topic><topic>NF-κB protein</topic><topic>Original Article</topic><topic>Promoter Regions, Genetic - drug effects</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Transcription Factor RelA - genetics</topic><topic>Transcriptomes</topic><topic>Tumor cells</topic><topic>Tumor Hypoxia - drug effects</topic><topic>Tumor microenvironment</topic><topic>Tumor Microenvironment - drug effects</topic><topic>Tumor Microenvironment - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salviano Soares de Amorim, Ísis</creatorcontrib><creatorcontrib>Rodrigues, Juliana Alves</creatorcontrib><creatorcontrib>Nicolau, Pedro</creatorcontrib><creatorcontrib>König, Sandra</creatorcontrib><creatorcontrib>Panis, Carolina</creatorcontrib><creatorcontrib>de Souza da Fonseca, Adenilson</creatorcontrib><creatorcontrib>Mencalha, Andre Luiz</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Molecular biology reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Salviano Soares de Amorim, Ísis</au><au>Rodrigues, Juliana Alves</au><au>Nicolau, Pedro</au><au>König, Sandra</au><au>Panis, Carolina</au><au>de Souza da Fonseca, Adenilson</au><au>Mencalha, Andre Luiz</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-Aza-2’-deoxycytidine induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment</atitle><jtitle>Molecular biology reports</jtitle><stitle>Mol Biol Rep</stitle><addtitle>Mol Biol Rep</addtitle><date>2021-02-01</date><risdate>2021</risdate><volume>48</volume><issue>2</issue><spage>1161</spage><epage>1169</epage><pages>1161-1169</pages><issn>0301-4851</issn><eissn>1573-4978</eissn><abstract>Hypoxia is associated with tumor aggressiveness and poor prognosis, including breast cancer. Low oxygen levels induces global genomic hypomethylation and hypermethylation of specific loci in tumor cells. DNA methylation is a reversible epigenetic modification, usually associated with gene silencing, contributing to carcinogenesis and tumor progression. Since the effects of DNA methyltransferase inhibitor are context-dependent and as there is little data comparing their molecular effects in normoxic and hypoxic microenvironments in breast cancer, this study aimed to understand the gene expression profiles and molecular effects in response to treatment with DNA methyltransferase inhibitor in normoxia and hypoxia, using the breast cancer model. For this, a cDNA microarray was used to analyze the changes in the transcriptome upon treatment with DNA methyltransferase inhibitor (5-Aza-2’-deoxycytidine: 5-Aza-2’-dC), in normoxia and hypoxia. Furthermore, immunocytochemistry was performed to investigate the effect of 5-Aza-2’-dC on NF-κB/p65 inflammation regulator subcellular localization and expression, in normoxia and hypoxia conditions. We observed that proinflammatory pathways were upregulated by treatment with 5-Aza-2’-dC, in both conditions. However, treatment with 5-Aza-2’-dC in normoxia showed a greater amount of overexpressed proinflammatory pathways than 5-Aza-2’-dC in hypoxia. In this sense, we observed that the NF-κB expression increased only upon 5-Aza-2’-dC in normoxia. Moreover, nuclear staining for NF-κB and NF-κB target genes upregulation,
IL1A
and
IL1B
, were also observed after 5-Aza-2’-dC in normoxia. Our results suggest that 5-Aza-2’-dC induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment. These data may support further studies and expand the understanding of the DNA methyltransferase inhibitor effects in different tumor contexts.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>33547534</pmid><doi>10.1007/s11033-020-05931-4</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-4139-4080</orcidid><orcidid>https://orcid.org/0000-0002-2762-1400</orcidid><orcidid>https://orcid.org/0000-0002-0104-4369</orcidid><orcidid>https://orcid.org/0000-0003-3322-2120</orcidid><orcidid>https://orcid.org/0000-0002-4441-4008</orcidid><orcidid>https://orcid.org/0000-0002-9400-076X</orcidid><orcidid>https://orcid.org/0000-0003-3229-8094</orcidid></addata></record> |
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| subjects | Acetylation - drug effects Animal Anatomy Animal Biochemistry Biomedical and Life Sciences Breast cancer Carcinogenesis Cell Line, Tumor Decitabine - pharmacology Deoxyribonucleic acid DNA DNA methylation DNA Methylation - drug effects DNA methyltransferase DNA microarrays DNA Modification Methylases - antagonists & inhibitors DNA Modification Methylases - genetics Enzyme Inhibitors - pharmacology Epigenesis, Genetic - genetics Epigenetics Gene expression Gene silencing Histology Humans Hypoxia IL-1β Immunocytochemistry Inflammation Inflammation - chemically induced Inflammation - genetics Inflammation - pathology Interleukin 1 Life Sciences Localization Morphology NF-κB protein Original Article Promoter Regions, Genetic - drug effects Promoter Regions, Genetic - genetics Transcription Factor RelA - genetics Transcriptomes Tumor cells Tumor Hypoxia - drug effects Tumor microenvironment Tumor Microenvironment - drug effects Tumor Microenvironment - genetics |
| title | 5-Aza-2’-deoxycytidine induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment |
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