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DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues...
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| Published in: | PloS one 2012-02, Vol.7 (2), p.e31507 |
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| creator | Zhang, Geng Schetter, Aaron He, Peijun Funamizu, Naotake Gaedcke, Jochen Ghadimi, B Michael Ried, Thomas Hassan, Raffit Yfantis, Harris G Lee, Dong H Lacy, Curtis Maitra, Anirban Hanna, Nader Alexander, H Richard Hussain, S Perwez |
| description | Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T:N ratio ∼0.1, P |
| doi_str_mv | 10.1371/journal.pone.0031507 |
| format | article |
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To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T:N ratio ∼0.1, P<0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = -0.35, P = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24-0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27-0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0031507</identifier><identifier>PMID: 22363658</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenocarcinoma ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biology ; Breast cancer ; Cancer ; Cancer therapies ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - mortality ; Carcinoma, Pancreatic Ductal - pathology ; Cell adhesion & migration ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell growth ; Cell Line, Tumor ; Chemotherapy ; Chromosomes ; Cohort Studies ; Comparative analysis ; Correlation coefficient ; Correlation coefficients ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - pharmacology ; Deoxycytidine - therapeutic use ; Dipeptidase ; Dipeptidases - genetics ; Dipeptidases - metabolism ; DNA microarrays ; Epidermal growth factor ; Female ; Gemcitabine ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene regulation ; Genes ; Genetic aspects ; Genetic Association Studies ; Genomics ; GPI-Linked Proteins - genetics ; GPI-Linked Proteins - metabolism ; Humans ; Invasiveness ; Laboratories ; Male ; MAP Kinase Signaling System - drug effects ; Maryland - epidemiology ; Medical research ; Medicine ; Microtubule-Associated Proteins - genetics ; Microtubule-Associated Proteins - metabolism ; Middle Aged ; Mortality ; Neoplasm Invasiveness ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Oligonucleotide Array Sequence Analysis ; Oxidative stress ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - mortality ; Pancreatic Neoplasms - pathology ; Pathology ; Patient outcomes ; Patients ; Prognosis ; Proportional Hazards Models ; Quality ; Reproducibility of Results ; Surgery ; Tissues ; Treatment Outcome ; Tumor cells ; Tumors</subject><ispartof>PloS one, 2012-02, Vol.7 (2), p.e31507</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-f5f79abbd3a1f5af8181dd29a15e1ed35016ead913a2d061b23ee498a1e84b983</citedby><cites>FETCH-LOGICAL-c691t-f5f79abbd3a1f5af8181dd29a15e1ed35016ead913a2d061b23ee498a1e84b983</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1323856483/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1323856483?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22363658$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>El-Rifai, Wael</contributor><creatorcontrib>Zhang, Geng</creatorcontrib><creatorcontrib>Schetter, Aaron</creatorcontrib><creatorcontrib>He, Peijun</creatorcontrib><creatorcontrib>Funamizu, Naotake</creatorcontrib><creatorcontrib>Gaedcke, Jochen</creatorcontrib><creatorcontrib>Ghadimi, B Michael</creatorcontrib><creatorcontrib>Ried, Thomas</creatorcontrib><creatorcontrib>Hassan, Raffit</creatorcontrib><creatorcontrib>Yfantis, Harris G</creatorcontrib><creatorcontrib>Lee, Dong H</creatorcontrib><creatorcontrib>Lacy, Curtis</creatorcontrib><creatorcontrib>Maitra, Anirban</creatorcontrib><creatorcontrib>Hanna, Nader</creatorcontrib><creatorcontrib>Alexander, H Richard</creatorcontrib><creatorcontrib>Hussain, S Perwez</creatorcontrib><title>DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T:N ratio ∼0.1, P<0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = -0.35, P = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24-0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27-0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments.</description><subject>Adenocarcinoma</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biology</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - mortality</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell adhesion & migration</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Chromosomes</subject><subject>Cohort Studies</subject><subject>Comparative analysis</subject><subject>Correlation coefficient</subject><subject>Correlation coefficients</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - pharmacology</subject><subject>Deoxycytidine - therapeutic use</subject><subject>Dipeptidase</subject><subject>Dipeptidases - genetics</subject><subject>Dipeptidases - metabolism</subject><subject>DNA microarrays</subject><subject>Epidermal growth factor</subject><subject>Female</subject><subject>Gemcitabine</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Association Studies</subject><subject>Genomics</subject><subject>GPI-Linked Proteins - genetics</subject><subject>GPI-Linked Proteins - metabolism</subject><subject>Humans</subject><subject>Invasiveness</subject><subject>Laboratories</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Maryland - epidemiology</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Microtubule-Associated Proteins - genetics</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Neoplasm Invasiveness</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Oxidative stress</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - mortality</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pathology</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>Prognosis</subject><subject>Proportional Hazards Models</subject><subject>Quality</subject><subject>Reproducibility of Results</subject><subject>Surgery</subject><subject>Tissues</subject><subject>Treatment Outcome</subject><subject>Tumor cells</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk2-L1DAQxoso3nn6DUQLgiC4a9M0bfpGOM5TFw7u8N_bME2m2yxtsibp4r32i5u77R1bUJC8SJj5PU8mQyZJnpNsSWhF3m3s6Az0y601uMwySlhWPUiOSU3zRZln9OHB-Sh54v0myxjlZfk4OcpzWtKS8ePk94er8yuSatPpRgefhnGwLpXY9zG2A693aND7tymaDoxEn8oOB-vReB30TofrFIxKtw6VllEve220hD61Y5B2wOiSbqPQIQQtUzXKEJOg0FgJTmpjB3iaPGqh9_hs2k-S7x_Pv519XlxcflqdnV4sZFmTsGhZW9XQNIoCaRm0nHCiVF4DYUhQUZaREkHVhEKuspI0OUUsag4EedHUnJ4kL_e-2956MfXPC0JzyllZcBqJ1Z5QFjZi6_QA7lpY0OI2YN1agIvv6FHwusScVpJxxguOhFeqqIu2zrOGlrzA6PV-um1sBlQSTXDQz0znGaM7sbY7QXOeV4xFg1eTgbM_R_ThHyVP1BpiVdq0NprJQXspTouqyhint17Lv1BxKRy0jD-o1TE-E7yZCSIT8FdYw-i9WH398v_s5Y85-_qA7RD60Hnbj0Fb4-dgsQels947bO87RzJxMwB33RA3AyCmAYiyF4ddvxfd_Xj6B-LuAt4</recordid><startdate>20120220</startdate><enddate>20120220</enddate><creator>Zhang, Geng</creator><creator>Schetter, Aaron</creator><creator>He, Peijun</creator><creator>Funamizu, Naotake</creator><creator>Gaedcke, Jochen</creator><creator>Ghadimi, B Michael</creator><creator>Ried, Thomas</creator><creator>Hassan, Raffit</creator><creator>Yfantis, Harris G</creator><creator>Lee, Dong H</creator><creator>Lacy, Curtis</creator><creator>Maitra, Anirban</creator><creator>Hanna, Nader</creator><creator>Alexander, H Richard</creator><creator>Hussain, S Perwez</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>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>20120220</creationdate><title>DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma</title><author>Zhang, Geng ; Schetter, Aaron ; He, Peijun ; Funamizu, Naotake ; Gaedcke, Jochen ; Ghadimi, B Michael ; Ried, Thomas ; Hassan, Raffit ; Yfantis, Harris G ; Lee, Dong H ; Lacy, Curtis ; Maitra, Anirban ; Hanna, Nader ; Alexander, H Richard ; Hussain, S Perwez</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-f5f79abbd3a1f5af8181dd29a15e1ed35016ead913a2d061b23ee498a1e84b983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenocarcinoma</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biology</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Carcinoma, Pancreatic Ductal - drug therapy</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - mortality</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cell adhesion & migration</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Chromosomes</topic><topic>Cohort Studies</topic><topic>Comparative analysis</topic><topic>Correlation coefficient</topic><topic>Correlation coefficients</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - pharmacology</topic><topic>Deoxycytidine - therapeutic use</topic><topic>Dipeptidase</topic><topic>Dipeptidases - genetics</topic><topic>Dipeptidases - metabolism</topic><topic>DNA microarrays</topic><topic>Epidermal growth factor</topic><topic>Female</topic><topic>Gemcitabine</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene regulation</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic Association Studies</topic><topic>Genomics</topic><topic>GPI-Linked Proteins - genetics</topic><topic>GPI-Linked Proteins - metabolism</topic><topic>Humans</topic><topic>Invasiveness</topic><topic>Laboratories</topic><topic>Male</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Maryland - epidemiology</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Microtubule-Associated Proteins - genetics</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Neoplasm Invasiveness</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Oxidative stress</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - mortality</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pathology</topic><topic>Patient outcomes</topic><topic>Patients</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Quality</topic><topic>Reproducibility of Results</topic><topic>Surgery</topic><topic>Tissues</topic><topic>Treatment Outcome</topic><topic>Tumor cells</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Geng</creatorcontrib><creatorcontrib>Schetter, Aaron</creatorcontrib><creatorcontrib>He, Peijun</creatorcontrib><creatorcontrib>Funamizu, Naotake</creatorcontrib><creatorcontrib>Gaedcke, Jochen</creatorcontrib><creatorcontrib>Ghadimi, B Michael</creatorcontrib><creatorcontrib>Ried, Thomas</creatorcontrib><creatorcontrib>Hassan, Raffit</creatorcontrib><creatorcontrib>Yfantis, Harris G</creatorcontrib><creatorcontrib>Lee, Dong H</creatorcontrib><creatorcontrib>Lacy, Curtis</creatorcontrib><creatorcontrib>Maitra, Anirban</creatorcontrib><creatorcontrib>Hanna, Nader</creatorcontrib><creatorcontrib>Alexander, H Richard</creatorcontrib><creatorcontrib>Hussain, S Perwez</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)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest 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</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>ProQuest Biological Science Journals</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>Open Access: DOAJ - Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Geng</au><au>Schetter, Aaron</au><au>He, Peijun</au><au>Funamizu, Naotake</au><au>Gaedcke, Jochen</au><au>Ghadimi, B Michael</au><au>Ried, Thomas</au><au>Hassan, Raffit</au><au>Yfantis, Harris G</au><au>Lee, Dong H</au><au>Lacy, Curtis</au><au>Maitra, Anirban</au><au>Hanna, Nader</au><au>Alexander, H Richard</au><au>Hussain, S Perwez</au><au>El-Rifai, Wael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-02-20</date><risdate>2012</risdate><volume>7</volume><issue>2</issue><spage>e31507</spage><pages>e31507-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T:N ratio ∼0.1, P<0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = -0.35, P = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24-0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27-0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22363658</pmid><doi>10.1371/journal.pone.0031507</doi><tpages>e31507</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-02, Vol.7 (2), p.e31507 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1323856483 |
| source | Open Access: PubMed Central; Publicly Available Content Database |
| subjects | Adenocarcinoma Adult Aged Aged, 80 and over Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biology Breast cancer Cancer Cancer therapies Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - mortality Carcinoma, Pancreatic Ductal - pathology Cell adhesion & migration Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell growth Cell Line, Tumor Chemotherapy Chromosomes Cohort Studies Comparative analysis Correlation coefficient Correlation coefficients Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology Deoxycytidine - therapeutic use Dipeptidase Dipeptidases - genetics Dipeptidases - metabolism DNA microarrays Epidermal growth factor Female Gemcitabine Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene regulation Genes Genetic aspects Genetic Association Studies Genomics GPI-Linked Proteins - genetics GPI-Linked Proteins - metabolism Humans Invasiveness Laboratories Male MAP Kinase Signaling System - drug effects Maryland - epidemiology Medical research Medicine Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Middle Aged Mortality Neoplasm Invasiveness Nuclear Proteins - genetics Nuclear Proteins - metabolism Oligonucleotide Array Sequence Analysis Oxidative stress Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - mortality Pancreatic Neoplasms - pathology Pathology Patient outcomes Patients Prognosis Proportional Hazards Models Quality Reproducibility of Results Surgery Tissues Treatment Outcome Tumor cells Tumors |
| title | DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma |
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