TY - JOUR
T1 - EphA2 expression is a key driver of migration and invasion and a poor prognostic marker in colorectal cancer
AU - Dunne, Philip D.
AU - Dasgupta, Sonali
AU - Blayney, Jaine K.
AU - McArt, Darragh G.
AU - Redmond, Keara L.
AU - Weir, Jessica Anne
AU - Bradley, Conor A.
AU - Sasazuki, Takehiko
AU - Shirasawa, Senji
AU - Wang, Tingting
AU - Srivastava, Supriya
AU - Ong, Chee Wee
AU - Arthur, Ken
AU - Salto-Tellez, Manuel
AU - Wilson, Richard H.
AU - Johnston, Patrick G.
AU - Van Schaeybroeck, Sandra
N1 - Funding Information:
The authors thank the patients and staff who took part in the Northern Ireland Adjuvant Chemotherapy trial, trial funders Wyeth Ltd (now Pfizer Inc.), and the Friends of the Cancer Centre. They also thank the Northern Ireland Biobank for its assistance in acquiring tissue for analysis and Nicola Totton for technical assistance. This work was financially supported by Cancer Research UK (C212/A7402) and Cancer Research UK fellowship (C13749/A7261). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
Copyright © 2015 AACR.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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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U2 - 10.1158/1078-0432.CCR-15-0603
DO - 10.1158/1078-0432.CCR-15-0603
M3 - Article
C2 - 26283684
AN - SCOPUS:84954526582
SN - 1078-0432
VL - 22
SP - 230
EP - 242
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -
