EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas
Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDACs) are well known. This study investigates genetic and epigenetic data together with tumor biology to find specific alterations responsible for metastasis formation. Using 16 human PDAC cell lines in a mu...
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| Veröffentlicht in: | International journal of cancer 2010-01, Vol.126 (1), p.114-124 |
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| container_title | International journal of cancer |
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| creator | Mees, Soeren Torge Mardin, Wolf Arif Wendel, Claudia Baeumer, Nicole Willscher, Edith Senninger, Norbert Schleicher, Christina Colombo‐Benkmann, Mario Haier, Joerg |
| description | Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDACs) are well known. This study investigates genetic and epigenetic data together with tumor biology to find specific alterations responsible for metastasis formation. Using 16 human PDAC cell lines in a murine orthotopic PDAC model, local infiltration and metastatic spread were assessed by standardized dissemination scores. The cell lines were further classified into 3 hierarchical groups according to their metastatic potential. Their mRNA and microRNA (miRNA) expression was profiled via mRNA‐microarray as well as Taqman Low Density Array, and validated by single quantitative RT‐PCR and Western blotting. In the highly metastatic group, a significant induction of EP300 targeting miRNAs miR‐194 (fold change: 26.88), miR‐200b (fold change: 61.65), miR‐200c (fold change: 19.44) and miR‐429 (fold change: 21.67) (p < 0.05) was detected. Corresponding to this, decreased expression of EP300 mRNA (p < 0.0001) and protein (p < 0.05) were detected in the highly metastatic PDAC cell lines with liver metastases compared to the nonmetastatic or marginally metastatic cell lines, while no correlation with local tumor growth was found. In conclusion, epigenetic alterations with upregulated EP300 targeting miRNAs miR‐194, miR‐200b, miR‐200c and miR‐429 are related to reduced EP300 mRNA and protein in PDAC. These results demonstrate that miRNAs might be able to modulate the expression of metastasis‐specific suppressor genes and metastatic behavior in PDAC, suggesting diagnostic and therapeutic opportunities for EP300 and its targeting miRNAs in PDAC. |
| doi_str_mv | 10.1002/ijc.24695 |
| format | Article |
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This study investigates genetic and epigenetic data together with tumor biology to find specific alterations responsible for metastasis formation. Using 16 human PDAC cell lines in a murine orthotopic PDAC model, local infiltration and metastatic spread were assessed by standardized dissemination scores. The cell lines were further classified into 3 hierarchical groups according to their metastatic potential. Their mRNA and microRNA (miRNA) expression was profiled via mRNA‐microarray as well as Taqman Low Density Array, and validated by single quantitative RT‐PCR and Western blotting. In the highly metastatic group, a significant induction of EP300 targeting miRNAs miR‐194 (fold change: 26.88), miR‐200b (fold change: 61.65), miR‐200c (fold change: 19.44) and miR‐429 (fold change: 21.67) (p < 0.05) was detected. Corresponding to this, decreased expression of EP300 mRNA (p < 0.0001) and protein (p < 0.05) were detected in the highly metastatic PDAC cell lines with liver metastases compared to the nonmetastatic or marginally metastatic cell lines, while no correlation with local tumor growth was found. In conclusion, epigenetic alterations with upregulated EP300 targeting miRNAs miR‐194, miR‐200b, miR‐200c and miR‐429 are related to reduced EP300 mRNA and protein in PDAC. These results demonstrate that miRNAs might be able to modulate the expression of metastasis‐specific suppressor genes and metastatic behavior in PDAC, suggesting diagnostic and therapeutic opportunities for EP300 and its targeting miRNAs in PDAC.</description><identifier>ISSN: 0020-7136</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.24695</identifier><identifier>PMID: 19569050</identifier><identifier>CODEN: IJCNAW</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Animals ; Biological and medical sciences ; Blotting, Western ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - pathology ; Cell Line, Tumor ; E1A-Associated p300 Protein - genetics ; epigenetics ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression Profiling ; Humans ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; metastasis ; metastasis suppressor genes ; Mice ; Mice, Nude ; microRNA ; MicroRNAs - genetics ; Neoplasm Metastasis - genetics ; Oligonucleotide Array Sequence Analysis ; pancreatic cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Tumors</subject><ispartof>International journal of cancer, 2010-01, Vol.126 (1), p.114-124</ispartof><rights>Copyright © 2009 UICC</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4875-dff8745708309dd57aec87982b54062b27b26587e2031b8162bf33df75b8b1433</citedby><cites>FETCH-LOGICAL-c4875-dff8745708309dd57aec87982b54062b27b26587e2031b8162bf33df75b8b1433</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fijc.24695$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fijc.24695$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22183963$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19569050$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mees, Soeren Torge</creatorcontrib><creatorcontrib>Mardin, Wolf Arif</creatorcontrib><creatorcontrib>Wendel, Claudia</creatorcontrib><creatorcontrib>Baeumer, Nicole</creatorcontrib><creatorcontrib>Willscher, Edith</creatorcontrib><creatorcontrib>Senninger, Norbert</creatorcontrib><creatorcontrib>Schleicher, Christina</creatorcontrib><creatorcontrib>Colombo‐Benkmann, Mario</creatorcontrib><creatorcontrib>Haier, Joerg</creatorcontrib><title>EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas</title><title>International journal of cancer</title><addtitle>Int J Cancer</addtitle><description>Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDACs) are well known. This study investigates genetic and epigenetic data together with tumor biology to find specific alterations responsible for metastasis formation. Using 16 human PDAC cell lines in a murine orthotopic PDAC model, local infiltration and metastatic spread were assessed by standardized dissemination scores. The cell lines were further classified into 3 hierarchical groups according to their metastatic potential. Their mRNA and microRNA (miRNA) expression was profiled via mRNA‐microarray as well as Taqman Low Density Array, and validated by single quantitative RT‐PCR and Western blotting. In the highly metastatic group, a significant induction of EP300 targeting miRNAs miR‐194 (fold change: 26.88), miR‐200b (fold change: 61.65), miR‐200c (fold change: 19.44) and miR‐429 (fold change: 21.67) (p < 0.05) was detected. Corresponding to this, decreased expression of EP300 mRNA (p < 0.0001) and protein (p < 0.05) were detected in the highly metastatic PDAC cell lines with liver metastases compared to the nonmetastatic or marginally metastatic cell lines, while no correlation with local tumor growth was found. In conclusion, epigenetic alterations with upregulated EP300 targeting miRNAs miR‐194, miR‐200b, miR‐200c and miR‐429 are related to reduced EP300 mRNA and protein in PDAC. These results demonstrate that miRNAs might be able to modulate the expression of metastasis‐specific suppressor genes and metastatic behavior in PDAC, suggesting diagnostic and therapeutic opportunities for EP300 and its targeting miRNAs in PDAC.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Line, Tumor</subject><subject>E1A-Associated p300 Protein - genetics</subject><subject>epigenetics</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>metastasis</subject><subject>metastasis suppressor genes</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>microRNA</subject><subject>MicroRNAs - genetics</subject><subject>Neoplasm Metastasis - genetics</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>pancreatic cancer</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Tumors</subject><issn>0020-7136</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1qFEEQgBsxmM3qwReQvojkMEn133TPcVmiJoQoouexp6cmdpg_u2aQ3PIIHnzCPImT7KInEQoKqj7q52PspYATASBP4004kTovzBO2ElDYDKQwT9lq6UFmhcoP2RHRDYAQBvQzdigKkxdgYMW-nn1UAPd3vza8i5-uNvd3PxNez62fsOYdTp6WiMRpHseEREPi19gjjz2v5zD5lvsa-yH4FGI_dJ740PDpG_LR9yGhp-fsoPEt4Yt9XrMvb88-b99nlx_enW83l1nQzpqsbhpntbHgFBR1bazH4GzhZGU05LKStpK5cRYlKFE5sZQaperGmspVQiu1Zm92c8c0fJ-RprKLFLBtfY_DTKXVOQilnfw_qbTQWiyXrNnxjgxpIErYlGOKnU-3pYDywXy5mC8fzS_sq_3Uueqw_kvuVS_A6z3gKfi2SYugSH84KYVTRf7wyOmO-xFbvP33xvL8Yrtb_RvYh5oe</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>Mees, Soeren Torge</creator><creator>Mardin, Wolf Arif</creator><creator>Wendel, Claudia</creator><creator>Baeumer, Nicole</creator><creator>Willscher, Edith</creator><creator>Senninger, Norbert</creator><creator>Schleicher, Christina</creator><creator>Colombo‐Benkmann, Mario</creator><creator>Haier, Joerg</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Blackwell</general><scope>IQODW</scope><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>7X8</scope><scope>7TM</scope></search><sort><creationdate>20100101</creationdate><title>EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas</title><author>Mees, Soeren Torge ; Mardin, Wolf Arif ; Wendel, Claudia ; Baeumer, Nicole ; Willscher, Edith ; Senninger, Norbert ; Schleicher, Christina ; Colombo‐Benkmann, Mario ; Haier, Joerg</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4875-dff8745708309dd57aec87982b54062b27b26587e2031b8162bf33df75b8b1433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cell Line, Tumor</topic><topic>E1A-Associated p300 Protein - genetics</topic><topic>epigenetics</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression Profiling</topic><topic>Humans</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>metastasis</topic><topic>metastasis suppressor genes</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>microRNA</topic><topic>MicroRNAs - genetics</topic><topic>Neoplasm Metastasis - genetics</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>pancreatic cancer</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mees, Soeren Torge</creatorcontrib><creatorcontrib>Mardin, Wolf Arif</creatorcontrib><creatorcontrib>Wendel, Claudia</creatorcontrib><creatorcontrib>Baeumer, Nicole</creatorcontrib><creatorcontrib>Willscher, Edith</creatorcontrib><creatorcontrib>Senninger, Norbert</creatorcontrib><creatorcontrib>Schleicher, Christina</creatorcontrib><creatorcontrib>Colombo‐Benkmann, Mario</creatorcontrib><creatorcontrib>Haier, Joerg</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mees, Soeren Torge</au><au>Mardin, Wolf Arif</au><au>Wendel, Claudia</au><au>Baeumer, Nicole</au><au>Willscher, Edith</au><au>Senninger, Norbert</au><au>Schleicher, Christina</au><au>Colombo‐Benkmann, Mario</au><au>Haier, Joerg</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>126</volume><issue>1</issue><spage>114</spage><epage>124</epage><pages>114-124</pages><issn>0020-7136</issn><eissn>1097-0215</eissn><coden>IJCNAW</coden><abstract>Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDACs) are well known. This study investigates genetic and epigenetic data together with tumor biology to find specific alterations responsible for metastasis formation. Using 16 human PDAC cell lines in a murine orthotopic PDAC model, local infiltration and metastatic spread were assessed by standardized dissemination scores. The cell lines were further classified into 3 hierarchical groups according to their metastatic potential. Their mRNA and microRNA (miRNA) expression was profiled via mRNA‐microarray as well as Taqman Low Density Array, and validated by single quantitative RT‐PCR and Western blotting. In the highly metastatic group, a significant induction of EP300 targeting miRNAs miR‐194 (fold change: 26.88), miR‐200b (fold change: 61.65), miR‐200c (fold change: 19.44) and miR‐429 (fold change: 21.67) (p < 0.05) was detected. Corresponding to this, decreased expression of EP300 mRNA (p < 0.0001) and protein (p < 0.05) were detected in the highly metastatic PDAC cell lines with liver metastases compared to the nonmetastatic or marginally metastatic cell lines, while no correlation with local tumor growth was found. In conclusion, epigenetic alterations with upregulated EP300 targeting miRNAs miR‐194, miR‐200b, miR‐200c and miR‐429 are related to reduced EP300 mRNA and protein in PDAC. These results demonstrate that miRNAs might be able to modulate the expression of metastasis‐specific suppressor genes and metastatic behavior in PDAC, suggesting diagnostic and therapeutic opportunities for EP300 and its targeting miRNAs in PDAC.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>19569050</pmid><doi>10.1002/ijc.24695</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Blotting, Western Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - pathology Cell Line, Tumor E1A-Associated p300 Protein - genetics epigenetics Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Profiling Humans Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences metastasis metastasis suppressor genes Mice Mice, Nude microRNA MicroRNAs - genetics Neoplasm Metastasis - genetics Oligonucleotide Array Sequence Analysis pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Reverse Transcriptase Polymerase Chain Reaction Tumors |
| title | EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas |
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