Role of EphB2/ephrin‑B1 signalling in the development and progression of obesity‑associated colorectal cancer

Suzuki,Yoshiyuki; Okabayashi,Koji; Hasegawa,Hirotoshi; Tsuruta,Masashi; Seishima,Ryo; Tokuda,Toshiki; Kitagawa,Yuko

doi:10.3892/ol.2022.13436

Role of EphB2/ephrin‑B1 signalling in the development and progression of obesity‑associated colorectal cancer

Authors:
- Yoshiyuki Suzuki
- Koji Okabayashi
- Hirotoshi Hasegawa
- Masashi Tsuruta
- Ryo Seishima
- Toshiki Tokuda
- Yuko Kitagawa
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Affiliations: Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
Published online on: July 19, 2022 https://doi.org/10.3892/ol.2022.13436
Article Number: 316
Copyright : © Suzuki et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Obesity is a major problem worldwide and has been associated with colorectal cancer development, among other diseases. Ephrin receptors and ligands play an important role in the turnover of the intestinal mucosa and intestinal crypt compartmentalization. It has been hypothesised that obesity‑induced inflammation affects ephrin signals, leading to carcinogenesis. Therefore, the aim of the present study was to assess the relationship between Eph‑ephrin B signalling, obesity and obesity‑associated colorectal cancer. An azoxymethane‑induced obesity‑associated cancer KKAy mouse model developed in our prior study was used. A total of 46 patients with consecutive colorectal cancer and 48 tumours were analysed. Immunohistological analyses were performed in mouse and human samples, and immunoreactive scores (IRS) were determined. KKAy mice were significantly more prone to cancer development compared with control C57/BL mice (2/15 in C57/BL vs. 10/10 in KKAy; P<0.001). TUNEL assay revealed a lower number of apoptotic cells in normal mucosa of KKAy mice (8.8% in C57/BL vs. 3.2% in KKAy; P<0.001) and obese patients (9.2% with BMI <25 vs. 3.6% with BMI ≥25; P=0.021). Immunohistological analysis revealed that ephrin‑B1 was downregulated in normal mucosa from KKAy mice and obese patients (IRS, 2.86 with BMI <25 vs. 6.00 with BMI ≥25; P=0.002). Moreover, EphB2 was downregulated in tumours from KKAy mice and obese patients (IRS, 6.58 with BMI <25 vs. 3.83 with BMI ≥25; P<0.001). The distribution of infiltrated macrophages corresponded to the MCP‑1 expression pattern in KKAy mice, and the number of macrophages was also significantly higher in those mice (36.3 in C57/BL vs. 120.0 in KKAy; P=0.029). The findings suggested that obesity results in disruption of EphB2/ephrin‑B1 signalling, promoting colorectal cancer development and progression.

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