Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway
Interleukin-6 (IL-6) has received particular attention in the pathogenesis of cervical cancer, although the underlying mechanism remains elusive. This study revealed that IL-6 promotes in vivo tumor growth of human cervical cancer C33A cells, but does not substantially alter their in vitro growth ki...
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| Veröffentlicht in: | Oncogene 2003-03, Vol.22 (10), p.1517-1527 |
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| creator | Wei, Lin-Hung Kuo, Min-Liang Chen, Chi-An Chou, Chia-Hung Lai, Kuo-Bau Lee, Chien-Nan Hsieh, Chang-Yao |
| description | Interleukin-6 (IL-6) has received particular attention in the pathogenesis of cervical cancer, although the underlying mechanism remains elusive. This study revealed that IL-6 promotes
in vivo
tumor growth of human cervical cancer C33A cells, but does not substantially alter their
in vitro
growth kinetics. The
in vivo
angiogenic assays showed that IL-6 increases angiogenic activity in human cervical cancer cells, an effect that is specifically associated with upregulation of vascular endothelial growth factor (VEGF). Also, using anti-VEGF antibody to block VEGF function significantly inhibited IL-6-mediated angiogenesis and tumor growth in nude mice, strongly supporting the critical role of VEGF in the IL-6-mediated cervical tumorigenesis. Accordingly, the signaling pathway downstream of IL-6/IL-6R responsible for the regulation of VEGF was investigated. Notably, pharmacological inhibition of PI3-K or MAPK failed to inhibit IL-6-mediated transcriptional upregulation of VEGF. Meanwhile, blocking STAT3 pathway with dominant-negative mutant STAT3D effectively abolished IL-6-induced VEGF mRNA. In transient transfections, a luciferase reporter construct containing the full-length 1.5-kb VEGF promoter or a 1.2-kb fragment lacking the known hypoxic-response element also exhibited the same degree of response to IL-6. Additionally, transient transfection of STAT3D downregulated the 1.2-kb VEGF promoter luciferase reporter stimulated by IL-6. Based on the above phenomenon combined with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer tissues, we conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway. |
| doi_str_mv | 10.1038/sj.onc.1206226 |
| format | Article |
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in vivo
tumor growth of human cervical cancer C33A cells, but does not substantially alter their
in vitro
growth kinetics. The
in vivo
angiogenic assays showed that IL-6 increases angiogenic activity in human cervical cancer cells, an effect that is specifically associated with upregulation of vascular endothelial growth factor (VEGF). Also, using anti-VEGF antibody to block VEGF function significantly inhibited IL-6-mediated angiogenesis and tumor growth in nude mice, strongly supporting the critical role of VEGF in the IL-6-mediated cervical tumorigenesis. Accordingly, the signaling pathway downstream of IL-6/IL-6R responsible for the regulation of VEGF was investigated. Notably, pharmacological inhibition of PI3-K or MAPK failed to inhibit IL-6-mediated transcriptional upregulation of VEGF. Meanwhile, blocking STAT3 pathway with dominant-negative mutant STAT3D effectively abolished IL-6-induced VEGF mRNA. In transient transfections, a luciferase reporter construct containing the full-length 1.5-kb VEGF promoter or a 1.2-kb fragment lacking the known hypoxic-response element also exhibited the same degree of response to IL-6. Additionally, transient transfection of STAT3D downregulated the 1.2-kb VEGF promoter luciferase reporter stimulated by IL-6. Based on the above phenomenon combined with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer tissues, we conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1206226</identifier><identifier>PMID: 12629515</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; Angiogenesis ; Animals ; Antibodies, Monoclonal - pharmacology ; Apoptosis ; Biological and medical sciences ; Carcinogenicity Tests ; Care and treatment ; Causes of ; Cell Biology ; Cell Division - genetics ; Cervical cancer ; Cervix ; Cervix Uteri - metabolism ; Chick Embryo ; Culture Media, Conditioned - pharmacology ; Cytokines ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Endothelial Growth Factors - genetics ; Endothelial Growth Factors - metabolism ; Enzyme Inhibitors - pharmacology ; Female ; Fundamental and applied biological sciences. Psychology ; Genetic aspects ; Gynecology ; Health aspects ; Human Genetics ; Human papillomavirus ; Humans ; Hypoxia ; Immune system ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Interleukin 6 ; Interleukin-6 - physiology ; Internal Medicine ; Kinases ; Lymphokines - drug effects ; Lymphokines - genetics ; Lymphokines - metabolism ; MAP kinase ; Medical schools ; Medicine ; Medicine & Public Health ; Mice ; Mice, Nude ; Molecular and cellular biology ; Neovascularization ; Neovascularization, Pathologic ; Obstetrics ; Oncology ; original-paper ; Pathogenesis ; Physiology ; Reference Values ; Risk factors ; Signal Transduction ; Stat3 protein ; STAT3 Transcription Factor ; Toxicology ; Trans-Activators - genetics ; Trans-Activators - metabolism ; Transcription ; Transfection ; Tumor Cells, Cultured ; Tumorigenesis ; Up-Regulation ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - pathology ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; Women</subject><ispartof>Oncogene, 2003-03, Vol.22 (10), p.1517-1527</ispartof><rights>Springer Nature Limited 2003</rights><rights>2003 INIST-CNRS</rights><rights>COPYRIGHT 2003 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 13, 2003</rights><rights>Nature Publishing Group 2003.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-392cba438b3e0928ce5bf0bb77a46a2171844fa9b57b79be55f7c072ddf483763</citedby><cites>FETCH-LOGICAL-c620t-392cba438b3e0928ce5bf0bb77a46a2171844fa9b57b79be55f7c072ddf483763</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.onc.1206226$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.onc.1206226$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14681040$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12629515$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wei, Lin-Hung</creatorcontrib><creatorcontrib>Kuo, Min-Liang</creatorcontrib><creatorcontrib>Chen, Chi-An</creatorcontrib><creatorcontrib>Chou, Chia-Hung</creatorcontrib><creatorcontrib>Lai, Kuo-Bau</creatorcontrib><creatorcontrib>Lee, Chien-Nan</creatorcontrib><creatorcontrib>Hsieh, Chang-Yao</creatorcontrib><title>Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Interleukin-6 (IL-6) has received particular attention in the pathogenesis of cervical cancer, although the underlying mechanism remains elusive. This study revealed that IL-6 promotes
in vivo
tumor growth of human cervical cancer C33A cells, but does not substantially alter their
in vitro
growth kinetics. The
in vivo
angiogenic assays showed that IL-6 increases angiogenic activity in human cervical cancer cells, an effect that is specifically associated with upregulation of vascular endothelial growth factor (VEGF). Also, using anti-VEGF antibody to block VEGF function significantly inhibited IL-6-mediated angiogenesis and tumor growth in nude mice, strongly supporting the critical role of VEGF in the IL-6-mediated cervical tumorigenesis. Accordingly, the signaling pathway downstream of IL-6/IL-6R responsible for the regulation of VEGF was investigated. Notably, pharmacological inhibition of PI3-K or MAPK failed to inhibit IL-6-mediated transcriptional upregulation of VEGF. Meanwhile, blocking STAT3 pathway with dominant-negative mutant STAT3D effectively abolished IL-6-induced VEGF mRNA. In transient transfections, a luciferase reporter construct containing the full-length 1.5-kb VEGF promoter or a 1.2-kb fragment lacking the known hypoxic-response element also exhibited the same degree of response to IL-6. Additionally, transient transfection of STAT3D downregulated the 1.2-kb VEGF promoter luciferase reporter stimulated by IL-6. Based on the above phenomenon combined with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer tissues, we conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Carcinogenicity Tests</subject><subject>Care and treatment</subject><subject>Causes of</subject><subject>Cell Biology</subject><subject>Cell Division - genetics</subject><subject>Cervical cancer</subject><subject>Cervix</subject><subject>Cervix Uteri - metabolism</subject><subject>Chick Embryo</subject><subject>Culture Media, Conditioned - pharmacology</subject><subject>Cytokines</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Endothelial Growth Factors - genetics</subject><subject>Endothelial Growth Factors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetic aspects</subject><subject>Gynecology</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Human papillomavirus</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Immune system</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - physiology</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Lymphokines - drug effects</subject><subject>Lymphokines - genetics</subject><subject>Lymphokines - metabolism</subject><subject>MAP kinase</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular and cellular biology</subject><subject>Neovascularization</subject><subject>Neovascularization, Pathologic</subject><subject>Obstetrics</subject><subject>Oncology</subject><subject>original-paper</subject><subject>Pathogenesis</subject><subject>Physiology</subject><subject>Reference Values</subject><subject>Risk factors</subject><subject>Signal Transduction</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor</subject><subject>Toxicology</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - metabolism</subject><subject>Transcription</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><subject>Tumorigenesis</subject><subject>Up-Regulation</subject><subject>Uterine Cervical Neoplasms - genetics</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A</subject><subject>Vascular Endothelial Growth Factors</subject><subject>Women</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kU1r3DAQhk1pabZprz0W0dLevNGXJeu4hCQNBHrotlchy2NHW1vaSnbC_vtqiWGhJAxiYPTMvDO8RfGR4DXBrL5Iu3Xwdk0oFpSKV8WKcCnKqlL8dbHCqsKlooyeFe9S2mGMpcL0bXFGqKCqItWq0Ld-gjjA_Mf5UqB9DGOYICEL8cFZM6BpHkNEfQyP0z1qDuj31c112cIefAt-Qsb3LvTgIbmEHpxBBv3cbrYM7c10_2gO74s3nRkSfFjyefHr-mp7-b28-3Fze7m5K62geCqZorYxnNUNA6xobaFqOtw0UhouDCWS1Jx3RjWVbKRqoKo6abGkbdvxmknBzotvT3PzBX9nSJMeXbIwDMZDmJMmtSRCSp7BL_-BuzBHn3fTVHDCGFG1ytTnFymKSc0IZadRvRlAO9-FKRp71NUbUiuaHzkKrp-hcrQwOhs8dC7Xn2uwMaQUodP76EYTD5pgfTRdp53OpuvF9NzwaVl2bkZoT_jicga-LoBJ2dMuGm9dOnFc1ARznLmLJy7lL99DPF39gvQ_FEDB7g</recordid><startdate>20030313</startdate><enddate>20030313</enddate><creator>Wei, Lin-Hung</creator><creator>Kuo, Min-Liang</creator><creator>Chen, Chi-An</creator><creator>Chou, Chia-Hung</creator><creator>Lai, Kuo-Bau</creator><creator>Lee, Chien-Nan</creator><creator>Hsieh, Chang-Yao</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20030313</creationdate><title>Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway</title><author>Wei, Lin-Hung ; Kuo, Min-Liang ; Chen, Chi-An ; Chou, Chia-Hung ; Lai, Kuo-Bau ; Lee, Chien-Nan ; Hsieh, Chang-Yao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c620t-392cba438b3e0928ce5bf0bb77a46a2171844fa9b57b79be55f7c072ddf483763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Carcinogenicity Tests</topic><topic>Care and treatment</topic><topic>Causes of</topic><topic>Cell Biology</topic><topic>Cell Division - genetics</topic><topic>Cervical cancer</topic><topic>Cervix</topic><topic>Cervix Uteri - metabolism</topic><topic>Chick Embryo</topic><topic>Culture Media, Conditioned - pharmacology</topic><topic>Cytokines</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Endothelial Growth Factors - genetics</topic><topic>Endothelial Growth Factors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetic aspects</topic><topic>Gynecology</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Human papillomavirus</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Immune system</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - physiology</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Lymphokines - drug effects</topic><topic>Lymphokines - genetics</topic><topic>Lymphokines - metabolism</topic><topic>MAP kinase</topic><topic>Medical schools</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Molecular and cellular biology</topic><topic>Neovascularization</topic><topic>Neovascularization, Pathologic</topic><topic>Obstetrics</topic><topic>Oncology</topic><topic>original-paper</topic><topic>Pathogenesis</topic><topic>Physiology</topic><topic>Reference Values</topic><topic>Risk factors</topic><topic>Signal Transduction</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor</topic><topic>Toxicology</topic><topic>Trans-Activators - 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This study revealed that IL-6 promotes
in vivo
tumor growth of human cervical cancer C33A cells, but does not substantially alter their
in vitro
growth kinetics. The
in vivo
angiogenic assays showed that IL-6 increases angiogenic activity in human cervical cancer cells, an effect that is specifically associated with upregulation of vascular endothelial growth factor (VEGF). Also, using anti-VEGF antibody to block VEGF function significantly inhibited IL-6-mediated angiogenesis and tumor growth in nude mice, strongly supporting the critical role of VEGF in the IL-6-mediated cervical tumorigenesis. Accordingly, the signaling pathway downstream of IL-6/IL-6R responsible for the regulation of VEGF was investigated. Notably, pharmacological inhibition of PI3-K or MAPK failed to inhibit IL-6-mediated transcriptional upregulation of VEGF. Meanwhile, blocking STAT3 pathway with dominant-negative mutant STAT3D effectively abolished IL-6-induced VEGF mRNA. In transient transfections, a luciferase reporter construct containing the full-length 1.5-kb VEGF promoter or a 1.2-kb fragment lacking the known hypoxic-response element also exhibited the same degree of response to IL-6. Additionally, transient transfection of STAT3D downregulated the 1.2-kb VEGF promoter luciferase reporter stimulated by IL-6. Based on the above phenomenon combined with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer tissues, we conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>12629515</pmid><doi>10.1038/sj.onc.1206226</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2003-03, Vol.22 (10), p.1517-1527 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_18716774 |
| source | MEDLINE; Nature Journals Online; SpringerLink (Online service); EZB Electronic Journals Library |
| subjects | 1-Phosphatidylinositol 3-kinase Angiogenesis Animals Antibodies, Monoclonal - pharmacology Apoptosis Biological and medical sciences Carcinogenicity Tests Care and treatment Causes of Cell Biology Cell Division - genetics Cervical cancer Cervix Cervix Uteri - metabolism Chick Embryo Culture Media, Conditioned - pharmacology Cytokines DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Endothelial Growth Factors - genetics Endothelial Growth Factors - metabolism Enzyme Inhibitors - pharmacology Female Fundamental and applied biological sciences. Psychology Genetic aspects Gynecology Health aspects Human Genetics Human papillomavirus Humans Hypoxia Immune system Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Interleukin 6 Interleukin-6 - physiology Internal Medicine Kinases Lymphokines - drug effects Lymphokines - genetics Lymphokines - metabolism MAP kinase Medical schools Medicine Medicine & Public Health Mice Mice, Nude Molecular and cellular biology Neovascularization Neovascularization, Pathologic Obstetrics Oncology original-paper Pathogenesis Physiology Reference Values Risk factors Signal Transduction Stat3 protein STAT3 Transcription Factor Toxicology Trans-Activators - genetics Trans-Activators - metabolism Transcription Transfection Tumor Cells, Cultured Tumorigenesis Up-Regulation Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - pathology Vascular endothelial growth factor Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Women |
| title | Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T18%3A07%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Interleukin-6%20promotes%20cervical%20tumor%20growth%20by%20VEGF-dependent%20angiogenesis%20via%20a%20STAT3%20pathway&rft.jtitle=Oncogene&rft.au=Wei,%20Lin-Hung&rft.date=2003-03-13&rft.volume=22&rft.issue=10&rft.spage=1517&rft.epage=1527&rft.pages=1517-1527&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/sj.onc.1206226&rft_dat=%3Cgale_proqu%3EA189218914%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=220183123&rft_id=info:pmid/12629515&rft_galeid=A189218914&rfr_iscdi=true |