Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells
MicroRNA-34a (miR-34a) is a transcriptional target of p53 and is down-regulated in pancreatic cancer. This study aimed to investigate the functional significance of miR-34a in pancreatic cancer progression through its epigenetic restoration with chromatin modulators, demethylating agent 5-Aza-2'...
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| Veröffentlicht in: | PloS one 2011-08, Vol.6 (8), p.e24099 |
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| creator | Nalls, Dara Tang, Su-Ni Rodova, Marianna Srivastava, Rakesh K Shankar, Sharmila |
| description | MicroRNA-34a (miR-34a) is a transcriptional target of p53 and is down-regulated in pancreatic cancer. This study aimed to investigate the functional significance of miR-34a in pancreatic cancer progression through its epigenetic restoration with chromatin modulators, demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) and HDAC inhibitor Vorinostat (SAHA).
Re-expression of miR-34a in human pancreatic cancer stem cells (CSCs) and in human pancreatic cancer cell lines upon treatment with 5-Aza-dC and SAHA strongly inhibited the cell proliferation, cell cycle progression, self-renewal, epithelial to mesenchymal transition (EMT) and invasion. In pancreatic CSCs, modulation of miR-34a induced apoptosis by activating caspase-3/7. Treatment of pancreatic CSCs with the chromatin-modulating agents resulted in the inhibition of Bcl-2, CDK6 and SIRT1, which are the putative targets of miR-34a. MiR-34a upregulation by these agents also induced acetylated p53, p21(WAF1), p27(KIP1) and PUMA in pancreatic CSCs. Inhibition of miR-34a by antagomiR abrogates the effects of 5-Aza-dC and SAHA, suggesting that 5-Aza-dC and SAHA regulate stem cell characteristics through miR-34a. In CSCs, SAHA inhibited Notch pathway, suggesting its suppression may contribute to inhibition of the self-renewal capacity and induction of apoptosis. Interestingly, treatment of pancreatic CSCs with SAHA resulted in the inhibition of EMT with the transcriptional up-regulation of E-Cadherin and down-regulation of N-Cadherin. Expression of EMT inducers (Zeb-1, Snail and Slug) was inhibited in CSCs upon treatment with SAHA. 5-Aza-dC and SAHA also retard in vitro migration and invasion of CSCs.
The present study thus demonstrates the role of miR-34a as a critical regulator of pancreatic cancer progression by the regulating CSC characteristics. The restoration of its expression by 5-Aza-dC and SAHA in CSCs will not only provide mechanistic insight and therapeutic targets for pancreatic cancer but also promising reagents to boost patient response to existing chemotherapies or as a standalone cancer drug by eliminating the CSC characteristics. |
| doi_str_mv | 10.1371/journal.pone.0024099 |
| format | Article |
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Re-expression of miR-34a in human pancreatic cancer stem cells (CSCs) and in human pancreatic cancer cell lines upon treatment with 5-Aza-dC and SAHA strongly inhibited the cell proliferation, cell cycle progression, self-renewal, epithelial to mesenchymal transition (EMT) and invasion. In pancreatic CSCs, modulation of miR-34a induced apoptosis by activating caspase-3/7. Treatment of pancreatic CSCs with the chromatin-modulating agents resulted in the inhibition of Bcl-2, CDK6 and SIRT1, which are the putative targets of miR-34a. MiR-34a upregulation by these agents also induced acetylated p53, p21(WAF1), p27(KIP1) and PUMA in pancreatic CSCs. Inhibition of miR-34a by antagomiR abrogates the effects of 5-Aza-dC and SAHA, suggesting that 5-Aza-dC and SAHA regulate stem cell characteristics through miR-34a. In CSCs, SAHA inhibited Notch pathway, suggesting its suppression may contribute to inhibition of the self-renewal capacity and induction of apoptosis. Interestingly, treatment of pancreatic CSCs with SAHA resulted in the inhibition of EMT with the transcriptional up-regulation of E-Cadherin and down-regulation of N-Cadherin. Expression of EMT inducers (Zeb-1, Snail and Slug) was inhibited in CSCs upon treatment with SAHA. 5-Aza-dC and SAHA also retard in vitro migration and invasion of CSCs.
The present study thus demonstrates the role of miR-34a as a critical regulator of pancreatic cancer progression by the regulating CSC characteristics. The restoration of its expression by 5-Aza-dC and SAHA in CSCs will not only provide mechanistic insight and therapeutic targets for pancreatic cancer but also promising reagents to boost patient response to existing chemotherapies or as a standalone cancer drug by eliminating the CSC characteristics.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0024099</identifier><identifier>PMID: 21909380</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Azacitidine - pharmacology ; Azacitidine - therapeutic use ; Azacytidine ; Bcl-2 protein ; Biology ; Biomarkers ; Breast cancer ; Cancer ; Cancer prevention ; Cancer therapies ; Care and treatment ; Caspase ; Caspase-3 ; Cell cycle ; Cell Cycle - drug effects ; Cell Cycle - genetics ; Cell growth ; Cell Line, Tumor ; Cell Movement - drug effects ; Cell proliferation ; Cell Proliferation - drug effects ; Cell self-renewal ; Chemotherapy ; Chromatin ; Chromatin - metabolism ; Cyclin-dependent kinase inhibitor p21 ; Cyclin-dependent kinase inhibitor p27 ; Departments ; Development and progression ; E-cadherin ; Epigenesis, Genetic - drug effects ; Epigenetic inheritance ; Epigenetics ; Epithelial-Mesenchymal Transition - drug effects ; Epithelial-Mesenchymal Transition - genetics ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene regulation ; Histone deacetylase ; Humans ; Hydroxamic Acids - pharmacology ; Hydroxamic Acids - therapeutic use ; Inhibition ; Laboratories ; Leukemia ; Medical prognosis ; Medicine ; Mesenchyme ; Metastasis ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Modulators ; Multiple myeloma ; Mutation ; N-Cadherin ; Neoplasm Invasiveness ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Notch protein ; p53 Protein ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Pathology ; Pharmacology ; Physiology ; Prostate cancer ; Reagents ; Restoration ; Ribonucleic acid ; RNA ; Scholarships & fellowships ; SIRT1 protein ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - metabolism ; Spheroids, Cellular - pathology ; Stem cells ; Toxicology ; Transcription ; Tumor cell lines ; Tumor proteins ; Tumor Stem Cell Assay ; Tumorigenesis ; Up-Regulation - drug effects ; Up-Regulation - genetics</subject><ispartof>PloS one, 2011-08, Vol.6 (8), p.e24099</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Nalls 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>Nalls et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-8c73be79a45a49e86ffb2407abb1e0a7b7847d6fb6b38a071e3fb76bdc09f54f3</citedby><cites>FETCH-LOGICAL-c757t-8c73be79a45a49e86ffb2407abb1e0a7b7847d6fb6b38a071e3fb76bdc09f54f3</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/PMC3166078/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166078/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21909380$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nalls, Dara</creatorcontrib><creatorcontrib>Tang, Su-Ni</creatorcontrib><creatorcontrib>Rodova, Marianna</creatorcontrib><creatorcontrib>Srivastava, Rakesh K</creatorcontrib><creatorcontrib>Shankar, Sharmila</creatorcontrib><title>Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>MicroRNA-34a (miR-34a) is a transcriptional target of p53 and is down-regulated in pancreatic cancer. This study aimed to investigate the functional significance of miR-34a in pancreatic cancer progression through its epigenetic restoration with chromatin modulators, demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) and HDAC inhibitor Vorinostat (SAHA).
Re-expression of miR-34a in human pancreatic cancer stem cells (CSCs) and in human pancreatic cancer cell lines upon treatment with 5-Aza-dC and SAHA strongly inhibited the cell proliferation, cell cycle progression, self-renewal, epithelial to mesenchymal transition (EMT) and invasion. In pancreatic CSCs, modulation of miR-34a induced apoptosis by activating caspase-3/7. Treatment of pancreatic CSCs with the chromatin-modulating agents resulted in the inhibition of Bcl-2, CDK6 and SIRT1, which are the putative targets of miR-34a. MiR-34a upregulation by these agents also induced acetylated p53, p21(WAF1), p27(KIP1) and PUMA in pancreatic CSCs. Inhibition of miR-34a by antagomiR abrogates the effects of 5-Aza-dC and SAHA, suggesting that 5-Aza-dC and SAHA regulate stem cell characteristics through miR-34a. In CSCs, SAHA inhibited Notch pathway, suggesting its suppression may contribute to inhibition of the self-renewal capacity and induction of apoptosis. Interestingly, treatment of pancreatic CSCs with SAHA resulted in the inhibition of EMT with the transcriptional up-regulation of E-Cadherin and down-regulation of N-Cadherin. Expression of EMT inducers (Zeb-1, Snail and Slug) was inhibited in CSCs upon treatment with SAHA. 5-Aza-dC and SAHA also retard in vitro migration and invasion of CSCs.
The present study thus demonstrates the role of miR-34a as a critical regulator of pancreatic cancer progression by the regulating CSC characteristics. The restoration of its expression by 5-Aza-dC and SAHA in CSCs will not only provide mechanistic insight and therapeutic targets for pancreatic cancer but also promising reagents to boost patient response to existing chemotherapies or as a standalone cancer drug by eliminating the CSC characteristics.</description><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Azacitidine - pharmacology</subject><subject>Azacitidine - therapeutic use</subject><subject>Azacytidine</subject><subject>Bcl-2 protein</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer prevention</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Caspase</subject><subject>Caspase-3</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Cycle - genetics</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell self-renewal</subject><subject>Chemotherapy</subject><subject>Chromatin</subject><subject>Chromatin - metabolism</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cyclin-dependent kinase inhibitor p27</subject><subject>Departments</subject><subject>Development and progression</subject><subject>E-cadherin</subject><subject>Epigenesis, Genetic - drug effects</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene regulation</subject><subject>Histone deacetylase</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Hydroxamic Acids - therapeutic use</subject><subject>Inhibition</subject><subject>Laboratories</subject><subject>Leukemia</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Mesenchyme</subject><subject>Metastasis</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>miRNA</subject><subject>Modulators</subject><subject>Multiple myeloma</subject><subject>Mutation</subject><subject>N-Cadherin</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Notch protein</subject><subject>p53 Protein</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pathology</subject><subject>Pharmacology</subject><subject>Physiology</subject><subject>Prostate cancer</subject><subject>Reagents</subject><subject>Restoration</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Scholarships & fellowships</subject><subject>SIRT1 protein</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - metabolism</subject><subject>Spheroids, Cellular - pathology</subject><subject>Stem cells</subject><subject>Toxicology</subject><subject>Transcription</subject><subject>Tumor cell lines</subject><subject>Tumor proteins</subject><subject>Tumor Stem Cell Assay</subject><subject>Tumorigenesis</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - genetics</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl-L1DAUxYso7rr6DUQLguDDjEnTJs2LsCz-GVhYWFdfQ5LedLK0zZik4uKXN3U6yxQVpA-9SX7n5OZysuw5RmtMGH5760Y_yG69cwOsESpKxPmD7BRzUqxogcjDo_okexLCLUIVqSl9nJ0UmCNOanSa_byRvoVohzaHnW1hSLXOPbRjJ6N1Q-5M3tvrFSllbpzPowcZexjidLCTg57WSaFTCT5Xd7kdtlbZg_ZPJETocw1dF55mj4zsAjyb_2fZlw_vby4-rS6vPm4uzi9XmlUsrmrNiALGZVnJkkNNjVHptUwqhQFJplhdsoYaRRWpJWIYiFGMqkYjbqrSkLPs5d5317kg5rkFgQliHOGK1onY7InGyVux87aX_k44acXvDedbIX16QwfCEF3jsmEV0KJM13CNDWKVwsgY2nCVvN7Nt42qh0anWXnZLUyXJ4PditZ9FwRTitjUzKvZwLtvI4T4j5ZnqpWpKzsYl8x0b4MW5yWjdY0LShK1_guVvgZ6q1NyjE37C8GbhSAxEX7EVo4hiM3n6_9nr74u2ddH7BZkF7fBdeOUk7AEyz2ovQvBg7mfHEZiCv5hGmIKvpiDn2Qvjqd-LzoknfwC08f_4Q</recordid><startdate>20110831</startdate><enddate>20110831</enddate><creator>Nalls, Dara</creator><creator>Tang, Su-Ni</creator><creator>Rodova, Marianna</creator><creator>Srivastava, Rakesh K</creator><creator>Shankar, Sharmila</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>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110831</creationdate><title>Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells</title><author>Nalls, Dara ; Tang, Su-Ni ; Rodova, Marianna ; Srivastava, Rakesh K ; Shankar, Sharmila</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-8c73be79a45a49e86ffb2407abb1e0a7b7847d6fb6b38a071e3fb76bdc09f54f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Azacitidine - pharmacology</topic><topic>Azacitidine - therapeutic use</topic><topic>Azacytidine</topic><topic>Bcl-2 protein</topic><topic>Biology</topic><topic>Biomarkers</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer prevention</topic><topic>Cancer therapies</topic><topic>Care and treatment</topic><topic>Caspase</topic><topic>Caspase-3</topic><topic>Cell cycle</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Cycle - genetics</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - drug effects</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell self-renewal</topic><topic>Chemotherapy</topic><topic>Chromatin</topic><topic>Chromatin - metabolism</topic><topic>Cyclin-dependent kinase inhibitor p21</topic><topic>Cyclin-dependent kinase inhibitor p27</topic><topic>Departments</topic><topic>Development and progression</topic><topic>E-cadherin</topic><topic>Epigenesis, Genetic - drug effects</topic><topic>Epigenetic inheritance</topic><topic>Epigenetics</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Epithelial-Mesenchymal Transition - genetics</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene regulation</topic><topic>Histone deacetylase</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Hydroxamic Acids - therapeutic use</topic><topic>Inhibition</topic><topic>Laboratories</topic><topic>Leukemia</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Mesenchyme</topic><topic>Metastasis</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>miRNA</topic><topic>Modulators</topic><topic>Multiple myeloma</topic><topic>Mutation</topic><topic>N-Cadherin</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Notch protein</topic><topic>p53 Protein</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pathology</topic><topic>Pharmacology</topic><topic>Physiology</topic><topic>Prostate cancer</topic><topic>Reagents</topic><topic>Restoration</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Scholarships & fellowships</topic><topic>SIRT1 protein</topic><topic>Spheroids, Cellular - drug effects</topic><topic>Spheroids, Cellular - metabolism</topic><topic>Spheroids, Cellular - pathology</topic><topic>Stem cells</topic><topic>Toxicology</topic><topic>Transcription</topic><topic>Tumor cell lines</topic><topic>Tumor proteins</topic><topic>Tumor Stem Cell Assay</topic><topic>Tumorigenesis</topic><topic>Up-Regulation - drug effects</topic><topic>Up-Regulation - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nalls, Dara</creatorcontrib><creatorcontrib>Tang, Su-Ni</creatorcontrib><creatorcontrib>Rodova, Marianna</creatorcontrib><creatorcontrib>Srivastava, Rakesh K</creatorcontrib><creatorcontrib>Shankar, Sharmila</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</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>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</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>Nalls, Dara</au><au>Tang, Su-Ni</au><au>Rodova, Marianna</au><au>Srivastava, Rakesh K</au><au>Shankar, Sharmila</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-08-31</date><risdate>2011</risdate><volume>6</volume><issue>8</issue><spage>e24099</spage><pages>e24099-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>MicroRNA-34a (miR-34a) is a transcriptional target of p53 and is down-regulated in pancreatic cancer. This study aimed to investigate the functional significance of miR-34a in pancreatic cancer progression through its epigenetic restoration with chromatin modulators, demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) and HDAC inhibitor Vorinostat (SAHA).
Re-expression of miR-34a in human pancreatic cancer stem cells (CSCs) and in human pancreatic cancer cell lines upon treatment with 5-Aza-dC and SAHA strongly inhibited the cell proliferation, cell cycle progression, self-renewal, epithelial to mesenchymal transition (EMT) and invasion. In pancreatic CSCs, modulation of miR-34a induced apoptosis by activating caspase-3/7. Treatment of pancreatic CSCs with the chromatin-modulating agents resulted in the inhibition of Bcl-2, CDK6 and SIRT1, which are the putative targets of miR-34a. MiR-34a upregulation by these agents also induced acetylated p53, p21(WAF1), p27(KIP1) and PUMA in pancreatic CSCs. Inhibition of miR-34a by antagomiR abrogates the effects of 5-Aza-dC and SAHA, suggesting that 5-Aza-dC and SAHA regulate stem cell characteristics through miR-34a. In CSCs, SAHA inhibited Notch pathway, suggesting its suppression may contribute to inhibition of the self-renewal capacity and induction of apoptosis. Interestingly, treatment of pancreatic CSCs with SAHA resulted in the inhibition of EMT with the transcriptional up-regulation of E-Cadherin and down-regulation of N-Cadherin. Expression of EMT inducers (Zeb-1, Snail and Slug) was inhibited in CSCs upon treatment with SAHA. 5-Aza-dC and SAHA also retard in vitro migration and invasion of CSCs.
The present study thus demonstrates the role of miR-34a as a critical regulator of pancreatic cancer progression by the regulating CSC characteristics. The restoration of its expression by 5-Aza-dC and SAHA in CSCs will not only provide mechanistic insight and therapeutic targets for pancreatic cancer but also promising reagents to boost patient response to existing chemotherapies or as a standalone cancer drug by eliminating the CSC characteristics.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21909380</pmid><doi>10.1371/journal.pone.0024099</doi><tpages>e24099</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-08, Vol.6 (8), p.e24099 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1307901568 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Apoptosis Apoptosis - drug effects Apoptosis - genetics Azacitidine - pharmacology Azacitidine - therapeutic use Azacytidine Bcl-2 protein Biology Biomarkers Breast cancer Cancer Cancer prevention Cancer therapies Care and treatment Caspase Caspase-3 Cell cycle Cell Cycle - drug effects Cell Cycle - genetics Cell growth Cell Line, Tumor Cell Movement - drug effects Cell proliferation Cell Proliferation - drug effects Cell self-renewal Chemotherapy Chromatin Chromatin - metabolism Cyclin-dependent kinase inhibitor p21 Cyclin-dependent kinase inhibitor p27 Departments Development and progression E-cadherin Epigenesis, Genetic - drug effects Epigenetic inheritance Epigenetics Epithelial-Mesenchymal Transition - drug effects Epithelial-Mesenchymal Transition - genetics Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene regulation Histone deacetylase Humans Hydroxamic Acids - pharmacology Hydroxamic Acids - therapeutic use Inhibition Laboratories Leukemia Medical prognosis Medicine Mesenchyme Metastasis MicroRNAs - genetics MicroRNAs - metabolism miRNA Modulators Multiple myeloma Mutation N-Cadherin Neoplasm Invasiveness Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Notch protein p53 Protein Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Pathology Pharmacology Physiology Prostate cancer Reagents Restoration Ribonucleic acid RNA Scholarships & fellowships SIRT1 protein Spheroids, Cellular - drug effects Spheroids, Cellular - metabolism Spheroids, Cellular - pathology Stem cells Toxicology Transcription Tumor cell lines Tumor proteins Tumor Stem Cell Assay Tumorigenesis Up-Regulation - drug effects Up-Regulation - genetics |
| title | Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells |
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