EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer
EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear. EphA2 expression was det...
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Veröffentlicht in: | Clinical cancer research 2016-01, Vol.22 (1), p.230-242 |
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creator | Dunne, Philip D Dasgupta, Sonali Blayney, Jaine K McArt, Darragh G Redmond, Keara L Weir, Jessica-Anne Bradley, Conor A Sasazuki, Takehiko Shirasawa, Senji Wang, Tingting Srivastava, Supriya Ong, Chee Wee Arthur, Ken Salto-Tellez, Manuel Wilson, Richard H Johnston, Patrick G Van Schaeybroeck, Sandra |
description | EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.
EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.
Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.
These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. |
doi_str_mv | 10.1158/1078-0432.CCR-15-0603 |
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EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.
Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.
These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-15-0603</identifier><identifier>PMID: 26283684</identifier><language>eng</language><publisher>United States</publisher><subject>Biomarkers, Tumor ; Cell Line, Tumor ; Cell Movement - genetics ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - mortality ; Colorectal Neoplasms - pathology ; Gene Expression ; Humans ; Kaplan-Meier Estimate ; Neoplasm Invasiveness ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Proto-Oncogene Proteins p21(ras) - genetics ; Proto-Oncogene Proteins p21(ras) - metabolism ; ral GTP-Binding Proteins - metabolism ; ral Guanine Nucleotide Exchange Factor - metabolism ; ras Proteins - metabolism ; Receptor, EphA2 - genetics ; Receptor, EphA2 - metabolism ; Reproducibility of Results ; Signal Transduction</subject><ispartof>Clinical cancer research, 2016-01, Vol.22 (1), p.230-242</ispartof><rights>2015 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-d906ee2e02d88819d32e9cae5b510dc714424944d377bf36c06ff1ab94a5a2083</citedby><cites>FETCH-LOGICAL-c529t-d906ee2e02d88819d32e9cae5b510dc714424944d377bf36c06ff1ab94a5a2083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26283684$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dunne, Philip D</creatorcontrib><creatorcontrib>Dasgupta, Sonali</creatorcontrib><creatorcontrib>Blayney, Jaine K</creatorcontrib><creatorcontrib>McArt, Darragh G</creatorcontrib><creatorcontrib>Redmond, Keara L</creatorcontrib><creatorcontrib>Weir, Jessica-Anne</creatorcontrib><creatorcontrib>Bradley, Conor A</creatorcontrib><creatorcontrib>Sasazuki, Takehiko</creatorcontrib><creatorcontrib>Shirasawa, Senji</creatorcontrib><creatorcontrib>Wang, Tingting</creatorcontrib><creatorcontrib>Srivastava, Supriya</creatorcontrib><creatorcontrib>Ong, Chee Wee</creatorcontrib><creatorcontrib>Arthur, Ken</creatorcontrib><creatorcontrib>Salto-Tellez, Manuel</creatorcontrib><creatorcontrib>Wilson, Richard H</creatorcontrib><creatorcontrib>Johnston, Patrick G</creatorcontrib><creatorcontrib>Van Schaeybroeck, Sandra</creatorcontrib><title>EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.
EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.
Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.
These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target.</description><subject>Biomarkers, Tumor</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Gene Expression</subject><subject>Humans</subject><subject>Kaplan-Meier Estimate</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Staging</subject><subject>Prognosis</subject><subject>Proportional Hazards Models</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>ral GTP-Binding Proteins - metabolism</subject><subject>ral Guanine Nucleotide Exchange Factor - metabolism</subject><subject>ras Proteins - metabolism</subject><subject>Receptor, EphA2 - genetics</subject><subject>Receptor, EphA2 - metabolism</subject><subject>Reproducibility of Results</subject><subject>Signal Transduction</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkVtP3DAQha2qqFx_AsiPfQkd35L4pRJKt7AqCITg2fI6k8Vt1t7a2VX59ySCReVpZjTnnBnpI-SUwTljqv7GoKoLkIKfN819wVQBJYhP5IApVRWCl-rz2O80--Qw598ATDKQX8g-L3ktyloekH62frrgdPZvnTBnHwOdZ2rpL3ymP5LfYqKxozd-mewwLW1o6Txsbd4Nlt7FmOhdissQ8-AdvbHpz2jzgTaxjwndYHva2OAwHZO9zvYZT97qEXn8OXtororr28t5c3FdOMX1ULQaSkSOwNu6rpluBUftLKqFYtC6iknJpZayFVW16ETpoOw6ZhdaWmU51OKIfH_NXW8WK2wdhiHZ3qyTX9n0bKL15uMm-CezjFsjSy1BwBjw9S0gxb8bzINZ-eyw723AuMmGVUqCFlpNUvUqdSnmnLB7P8PATKTMRMFMFMxIyjBlJlKj7-z_H99dOzTiBUrlj6k</recordid><startdate>20160101</startdate><enddate>20160101</enddate><creator>Dunne, Philip D</creator><creator>Dasgupta, Sonali</creator><creator>Blayney, Jaine K</creator><creator>McArt, Darragh G</creator><creator>Redmond, Keara L</creator><creator>Weir, Jessica-Anne</creator><creator>Bradley, Conor A</creator><creator>Sasazuki, Takehiko</creator><creator>Shirasawa, Senji</creator><creator>Wang, Tingting</creator><creator>Srivastava, Supriya</creator><creator>Ong, Chee Wee</creator><creator>Arthur, Ken</creator><creator>Salto-Tellez, Manuel</creator><creator>Wilson, Richard H</creator><creator>Johnston, Patrick G</creator><creator>Van Schaeybroeck, Sandra</creator><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>5PM</scope></search><sort><creationdate>20160101</creationdate><title>EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer</title><author>Dunne, Philip D ; Dasgupta, Sonali ; Blayney, Jaine K ; McArt, Darragh G ; Redmond, Keara L ; Weir, Jessica-Anne ; Bradley, Conor A ; Sasazuki, Takehiko ; Shirasawa, Senji ; Wang, Tingting ; Srivastava, Supriya ; Ong, Chee Wee ; Arthur, Ken ; Salto-Tellez, Manuel ; Wilson, Richard H ; Johnston, Patrick G ; Van Schaeybroeck, Sandra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-d906ee2e02d88819d32e9cae5b510dc714424944d377bf36c06ff1ab94a5a2083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Biomarkers, Tumor</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - genetics</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Gene Expression</topic><topic>Humans</topic><topic>Kaplan-Meier Estimate</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Staging</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>ral GTP-Binding Proteins - metabolism</topic><topic>ral Guanine Nucleotide Exchange Factor - metabolism</topic><topic>ras Proteins - metabolism</topic><topic>Receptor, EphA2 - genetics</topic><topic>Receptor, EphA2 - metabolism</topic><topic>Reproducibility of Results</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dunne, Philip D</creatorcontrib><creatorcontrib>Dasgupta, Sonali</creatorcontrib><creatorcontrib>Blayney, Jaine K</creatorcontrib><creatorcontrib>McArt, Darragh G</creatorcontrib><creatorcontrib>Redmond, Keara L</creatorcontrib><creatorcontrib>Weir, Jessica-Anne</creatorcontrib><creatorcontrib>Bradley, Conor A</creatorcontrib><creatorcontrib>Sasazuki, Takehiko</creatorcontrib><creatorcontrib>Shirasawa, Senji</creatorcontrib><creatorcontrib>Wang, Tingting</creatorcontrib><creatorcontrib>Srivastava, Supriya</creatorcontrib><creatorcontrib>Ong, Chee Wee</creatorcontrib><creatorcontrib>Arthur, Ken</creatorcontrib><creatorcontrib>Salto-Tellez, Manuel</creatorcontrib><creatorcontrib>Wilson, Richard H</creatorcontrib><creatorcontrib>Johnston, Patrick G</creatorcontrib><creatorcontrib>Van Schaeybroeck, Sandra</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dunne, Philip D</au><au>Dasgupta, Sonali</au><au>Blayney, Jaine K</au><au>McArt, Darragh G</au><au>Redmond, Keara L</au><au>Weir, Jessica-Anne</au><au>Bradley, Conor A</au><au>Sasazuki, Takehiko</au><au>Shirasawa, Senji</au><au>Wang, Tingting</au><au>Srivastava, Supriya</au><au>Ong, Chee Wee</au><au>Arthur, Ken</au><au>Salto-Tellez, Manuel</au><au>Wilson, Richard H</au><au>Johnston, Patrick G</au><au>Van Schaeybroeck, Sandra</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2016-01-01</date><risdate>2016</risdate><volume>22</volume><issue>1</issue><spage>230</spage><epage>242</epage><pages>230-242</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.
EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.
Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.
These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target.</abstract><cop>United States</cop><pmid>26283684</pmid><doi>10.1158/1078-0432.CCR-15-0603</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Biomarkers, Tumor Cell Line, Tumor Cell Movement - genetics Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - mortality Colorectal Neoplasms - pathology Gene Expression Humans Kaplan-Meier Estimate Neoplasm Invasiveness Neoplasm Staging Prognosis Proportional Hazards Models Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism ral GTP-Binding Proteins - metabolism ral Guanine Nucleotide Exchange Factor - metabolism ras Proteins - metabolism Receptor, EphA2 - genetics Receptor, EphA2 - metabolism Reproducibility of Results Signal Transduction |
title | EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer |
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