Supplementary table 1. Clinical-pathological features of the resection-only and chemotherapy/resection stage II/III colorectal cancer patient cohorts with mature survival data in the Singapore dataset. Supplementary table 2. EphA2 and clinical-pathological correlates in CRC. Correlation between EphA2 and CD44, LGR5, CD133, Ki-67 and AXL in 509 stage I-IV CRC cases of the Singapore dataset. Supplementary table 3. Statistical associations between pairs of factors in the surgery only (A) and surgery/chemotherapy (B) stage II/III groups in the Singapore dataset. Supplementary table 4. A. Univariate and multivariate analysis (Cox proportional hazards regression) of resection-chemotherapy stage II/III patient group. B. Final multivariate model (Cox proportional hazards regression) of resection-chemotherapy stage II/III patient group. Supplementary table 5. Statistical association between expression levels of TGF-α and EphA2 using Spearman's Rank Correlation in GSE17536, GSE39582, GSE14333 and The Cancer Genome Atlas (TCGA). Within each dataset the value of Rho and associated p-value is reported.
ARTICLE ABSTRACT
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. Clin Cancer Res; 22(1); 230–42. ©2015 AACR.
