EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer.
OBJECTIVE
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.


METHODS
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.
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Philip D
PD
Dunne
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Sonali
S
Dasgupta
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Jaine K
JK
Blayney
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Darragh G
DG
McArt
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Keara L
KL
Redmond
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Jessica-Anne
JA
Weir
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Conor A
CA
Bradley
Institute for Advanced Study, Kyushu University, Fukuoka 812-8582, Higashi-ku, Japan.
Takehiko
T
Sasazuki
Department of Cell Biology, Faculty of Medicine, Fukuoka University, Jonan-Ku, Fukuoka 814-0180, Japan.
Senji
S
Shirasawa
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Tingting
T
Wang
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Supriya
S
Srivastava
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Chee Wee
CW
Ong
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Ken
K
Arthur
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Manuel
M
Salto-Tellez
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Richard H
RH
Wilson
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Patrick G
PG
Johnston
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.
Sandra
S
Van Schaeybroeck
D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D020725:ral GTP-Binding Proteins / Q000378:metabolism; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D020726:ral Guanine Nucleotide Exchange Factor; D036104:Receptor, EphA2; D016283:Proto-Oncogene Proteins p21(ras); D020725:ral GTP-Binding Proteins; D018631:ras Proteins