J Pathol Transl Med.  2018 Sep;52(5):298-306. 10.4132/jptm.2018.06.29.

Prognostic Significance of EPHB2 Expression in Colorectal Cancer Progression

• Jang BG
• Kim HS
• Chang WY
• Bae JM
• Kang GH

• KMID: 2422096
• DOI: http://doi.org/10.4132/jptm.2018.06.29

Abstract

BACKGROUND
A receptor tyrosine kinase for ephrin ligands, EPHB2, is expressed in normal colorectal tissues and colorectal cancers (CRCs). The aim of this study was to investigate EPHB2 expression over CRC progression and determine its prognostic significance in CRC.
METHODS
To measure EPHB2 mRNA and protein expression, real-time polymerase chain reaction and immunohistochemistry were performed in 32 fresh-frozen and 567 formalin-fixed paraffin-embedded CRC samples, respectively. We further investigated clinicopathological features and overall and recurrence-free survival according to EPHB2 protein expression.
RESULTS
The EPHB2 level was upregulated in CRC samples compared to non-cancerous tissue in most samples and showed a strong positive correlation with AXIN2. Notably, CD44 had a positive association with both mRNA and protein levels of EPHB2. Immunohistochemical analysis revealed no difference in EPHB2 expression between adenoma and carcinoma areas. Although EPHB2 expression was slightly lower in invasive fronts compared to surface area (p < .05), there was no difference between superficial and metastatic areas. EPHB2 positivity was associated with lymphatic (p < .001) and venous (p = .001) invasion, TNM stage (p < .001), and microsatellite instability (p = .036). Kaplan-Meier analysis demonstrated that CRC patients with EPHB2 positivity showed better clinical outcomes in both overall (p = .049) and recurrence-free survival (p = .015). However, multivariate analysis failed to show that EPHB2 is an independent prognostic marker in CRCs (hazard ratio, 0.692; p = .692).
CONCLUSIONS
Our results suggest that EPHB2 is overexpressed in a subset of CRCs and is a significant prognostic marker.

Keyword

EPHB2; Colorectal neoplasms; Immunohistochemistry; Prognosis

MeSH Terms

Adenoma
Colorectal Neoplasms*
Humans
Immunohistochemistry
Ligands
Microsatellite Instability
Multivariate Analysis
Prognosis
Protein-Tyrosine Kinases
Real-Time Polymerase Chain Reaction
Receptor, EphB2
RNA, Messenger
Ligands
Protein-Tyrosine Kinases
RNA, Messenger
Receptor, EphB2

Figure

• 

  Fig. 1. EPHB2 expression in colorectal cancers (CRCs) and matched normal colon tissues. (A, B) Real-time polymerase chain reaction analysis of EPHB2 mRNA level in CRCs and corresponding non-cancerous mucosa (NCM). (C) A correlation between EPHB2 and AXIN2 expression. (D–G) Correlations between EPHB2 and candidate cancer stem cell markers.

• 

  Fig. 2. Representative cases showing high EPHB2 and CD44 expression (A–C) and low EPHB2 and CD44 expression (D–F) in colorectal cancers. (G) Scatter plot with a regression line showing a positive correlation between EPHB2 and CD44 expression. H-scores, Histoscores.

• 

  Fig. 3. Expression profile of EPHB2 during colorectal cancer (CRC) progression. (A, B) EPHB2 expression in adenoma and carcinoma portions in CRCs arising in pre-existing adenomas. (C–E) EPHB2 expression in three spots of ulcerofungating CRCs; superficial area, invasive fronts, and metastatic cancers. *p<.05. ns, not significant; AD, adenoma; CA, carcinoma; LN, lymph node metastasis; Cs, superficial cancer: Ci, invasive cancer.

• 

  Fig. 4. Representative cases showing negative EPHB2 and nuclear β-catenin expression (A–C) and positive EPHB2 and nuclear β-catenin (D–F) expression in colorectal cancers.

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  Fig. 5. Prognostic significance of EPHB2 expression in overall (A) and recurrence-free (B) survival in colorectal cancers.

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