N<sup>6</sup>‑methyladenosine reader insulin‑like growth factor 2 mRNA‑binding protein 2 promotes abnormal proliferation of colonic epithelial cells in type 2 diabetes mellitus by regulating midkine

Li,Jieyao; Xie,Qingsheng; Xu,Jihao

doi:10.3892/mmr.2026.13818

April-2026 Volume 33 Issue 4

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April-2026 Volume 33 Issue 4

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Article Open Access

N⁶‑methyladenosine reader insulin‑like growth factor 2 mRNA‑binding protein 2 promotes abnormal proliferation of colonic epithelial cells in type 2 diabetes mellitus by regulating midkine

Authors:
- Jieyao Li
- Qingsheng Xie
- Jihao Xu
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Affiliations: Department of Gastroenterology, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat‑Sen Memorial Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China

Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 108
|
Published online on: February 4, 2026

https://doi.org/10.3892/mmr.2026.13818
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Abstract

The present study aimed to elucidate abnormal proliferation of colonic epithelial cells in type 2 diabetes mellitus (T2DM), a potential early step in colonic carcinoma development. Analysis of normal adjacent colonic epithelium obtained from colonic carcinoma surgeries showed an increased proliferative index among patients with T2DM. In vitro, high‑glucose medium mimicking diabetic conditions enhanced the proliferation of NCM460 cells, a normal human colon mucosal epithelial cell line. To identify dysregulated N6‑methyladenosine modifiers, the present study analyzed RNA sequencing datasets from the GEO database and identified an upregulated expression of insulin‑like growth factor 2 mRNA binding protein 2 (IGF2BP2) in the colonic epithelium of patients with T2DM, which was subsequently confirmed in the clinical samples and in vitro. IGF2BP2 knockdown inhibited the high glucose‑induced proliferation. Further bioinformatic evidence suggested midkine (MDK) as a potential target of IGF2BP2. MDK upregulation was confirmed in colonic epithelium under T2DM conditions, and its knockdown also inhibited high glucose‑induced proliferation. Overexpression of MDK partially prevented the anti‑proliferative effect of IGF2BP2 knockdown. Mechanistically, IGF2BP2 knockdown reduced MDK mRNA stability. RNA immunoprecipitation confirmed that IGF2BP2 bound to MDK mRNA, and this binding was significantly diminished upon mutation of the top three predicted N6‑methyladenosine modification sites in MDK. These findings suggested that the IGF2BP2/MDK axis contributed to abnormal colonic epithelial proliferation under T2DM conditions and may represent a potential therapeutic target to reduce carcinoma risk in patients with diabetes.

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