Abstract
The protein tyrosine kinase Ephrin type-B receptor 3 (EPHB3) is expressed in cells at the base of intestinal crypts, acting as a cellular guide in the maintenance of intestinal crypt architecture. We aimed to investigate the expression profile of EPHB3 in colorectal precancerous lesions and colorectal cancers (CRCs), and assess its prognostic value. EPHB3 expression was higher in CRCs than in normal mucosa and was associated with the intestinal stem cell markers EPHB2, OLFM4, LRIG1, and a proposed cancer stem cell marker, CD44. Enhanced EPHB3 expression significantly declined during the transformation from adenoma to carcinoma and as the tumor invaded into deeper tissue layers. Namely, a substantial reduction of EPHB3 expression was observed in the budding cancer cells at the invasive tumor fronts, which was more extensive than E-cadherin downregulation. In an azoxymethane/dextran sulfate sodium-induced, colitis-associated, CRC model, EPHB3 expression increased along with tumor development. In a large cohort of CRC patients, EPHB3 positivity was observed in 24% of 610 CRCs and was negatively correlated with tumor differentiation, lympho-vascular invasion, and tumor, node, and metastasis stages. EPHB3 was positively associated with microsatellite instability but was associated with neither CpG island methylation, nor with KRAS and BRAF mutations. Notably, EPHB3 positivity was associated with better clinical outcomes, although it was not an independent prognostic marker. Overexpression of EPHB3 in the colon cancer cell line, DLD1, led to decreased cell growth and migration and reduced mitogen-activated protein kinase signaling. Taken together, our data demonstrate the suppressive role of EPHB3 in CRC progression.
Highlights
Ephrin type-B receptor 3 (EPHB3) is a member of the largest family of receptor tyrosine kinases, Eph [1]
Using tumor samples from a large cohort of colorectal cancers (CRCs) patients we demonstrated that EPHB3 expression is positively associated with less advanced tumor stages and better clinical outcomes
Enhanced EPHB3 expression in TAs declined during the transformation from adenoma to carcinoma, and it further decreased when the tumor began invading deeper into the muscular layers
Summary
Ephrin type-B receptor 3 (EPHB3) is a member of the largest family of receptor tyrosine kinases, Eph [1]. A wide variety of cancer cells express EPHB receptors and their cancer-related activities are complex and intriguing; their roles can be either tumor suppressive or oncogenic depending on the type of cancer and the cellular context [1,6]. EPHB3 is downregulated in advanced stages of human CRC [10], which suggests that EPHB3 functions as a tumor suppressor in this context. Due to the complex functions and bidirectional signaling of the EPH/ephrin system, this hypothesis needs to be verified with a large cohort of human CRC samples. Despite all the strong evidence supporting a tumor suppressive role for EPHB3 in mouse studies, Xaun et al recently reported that EPHB3 is an independent prognostic factor for poor survival in CRC patients [11]. There are conflicting data regarding the effect of EPHB3 on the progression of non-small cell lung cancer [12,13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
