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
Hauptverfasser: 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
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container_start_page 230
container_title Clinical cancer research
container_volume 22
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.
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however, its role in colorectal cancer recurrence and progression is unclear. 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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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